0163-769X/96/$03.00/0
Endocrine Reviews
Copyright © 1996 by The Endocrine Society
Vol. 17, No. 1
Printed in U.S.A.
Immune-Neuro-Endocrine Interactions: Facts and
Hypotheses
HUGO OSCAR BESEDOVSKY AND ADRIANA DEL REY
Division of Immunophysiology, Institute of Physiology, Medical Faculty, Deutschhausstrafie 2, D-35037
Marburg, Germany
I. Introduction
I. Introduction
II. Reciprocal Effects Between Immune and Neuro-Endocrine Mechanisms
A. Receptors for cytokines, hormones, neurotransmitters, and neuropeptides in immune, endocrine, and
neural cells
1. Receptors for hormones, neurotransmitters, and
neuropeptides in immune cells
2. Receptors for immune cytokines in endocrine
glands
3. Receptors for immune cytokines in the nervous
system
B. Immune and neuro-endocrine products coexist in
lymphoid, endocrine, and neural tissues
1. Neuro-endocrine agents in lymphoid organs
2. Immune cytokines in endocrine and nervous
systems
C. Hormones, neurotransmitters, and neuropeptides
can affect the immune system
1. Endocrine effects on the immune system
2. Neural effects on the immune system
3. Immune mechanisms that can be affected by
neuro-endocrine agents
D. Immune cell products can affect neuro-endocrine
mechanisms
1. Effects of immune-derived products on endocrine mechanisms
2. Effects of immune-derived products on the nervous system
3. Metabolic effects of cytokines
III. Immune-Neuro-Endocrine Circuits
A. Long loop immune-neuro-endocrine circuits
B. Immune-neuro-endocrine circuits operating at local
levels
C. Relevance of immune-neuro-endocrine circuits for
immunoregulation
IV. Homeostatic and Antihomeostatic Functions of the Immune System: Contribution to Natural Selection
V. Outlook
A. The immune system as a diffuse, sensorial receptor
organ
B. Is that all?
T
HE existence of mechanisms that provide immunity to
an infective agent was inferred from empirical observations obtained through the ingenuity and deductive capacity of early investigators. The first procedures for vaccinations and serotherapy resulted from these observations.
The implementation of these procedures, probably the most
important contribution of immunology to medical science,
was, at first, based on a very rudimentary knowledge of the
immune system. During the first half of the 20th century, this
rather primitive knowledge coincided with evidence showing that the endocrine and nervous systems integrate and
regulate different bodily functions. Therefore, based on some
supportive data, it was considered that immune mechanisms
may also be influenced by these systems. However, at the
beginning of the second half of the 20th century, most efforts
were directed at understanding the molecular and cellular
basis of the immune response and the mechanisms of acquisition of immunological diversity and self-tolerance. The
product of these studies is formidable. As a result, we know
the structure of the main molecules (e.g. antibodies, T cell
receptors) that allow recognition of antigens from inside and
outside the organism, as well as the types and subtypes of
cells that participate in an immune response. In addition, the
molecular and genetic basis of the differentiation and diversification of immunological cells is largely understood. Furthermore, our knowledge of the biochemical and molecular
basis of immune cell activation and how these cells interact
and receive information from antigen-presenting cells has
been clarified to a great extent. The existence of autoregulatory mechanisms that can control the immune response has
also been established. In contrast, much less is known about
how immunological cells and their products interact with
other bodily systems, and about the consequences of such
interactions for mechanisms intrinsic and extrinsic to the
immune system. Thus, the understanding of the organization
of the immune system itself has raised essential questions
concerning its physiological functioning within the whole
organism. The need to provide answers to these questions is
becoming increasingly important, and many laboratories are
now focused on understanding the functional and molecular
basis of interactions between the immune system and integrative neuro-endocrine mechanisms.
As we shall discuss later, interactions between the immune, endocrine, and nervous systems are necessarily complex since each of these systems is intrinsically complex.
Address reprint requests to: Hugo O. Besedovsky, M. D., Division of
Immunophysiology, Institute of Physiology, Medical Faculty,
Deutschhausstraj3e 2, D-35037 Marburg, Germany.
This work was supported by the Volkswagen Stiftung.
64
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
Furthermore, the amount of information that is now available is enormous, and, in some instances, contradictory or
^ difficult to interpret. Therefore, this article will not be an
exhaustive review of all the contributions from the multiple
laboratories engaged in this field of research. Instead, it will
provide an analysis of the available information within a
defined conceptual framework, which, even if it turns out to
be wrong in certain aspects, might serve to promote further
. research.
The main focus of this article will be on functional interactions between immune, neural, and endocrine cells and
their possible relevance to physiological and certain pathological processes. These interactions occur at so many levels
that it is necessary to establish some priorities and restrictions for the following discussion. We shall particularly high* light those studies of the effects of the products of immune
cells on neuro-endocrine functions since the existence of
afferent pathways from the immune system to mechanisms
under central nervous system (CNS) control is now being
intensively investigated. Certain aspects that will either be
absent or only briefly discussed include psychosocial influ• ences on immunity, neuroimmunological brain diseases, effects of immune cell products on behavior, thermoregulation
and sleep, and endocrine diseases caused by the immune
system. Molecular and subcellular processes underlying immune-neuro-endocrine interactions will not be discussed in
detail, unless it is necessary for understanding the biological
relevance of such interactions.
We shall often refer to cytokines as immune-derived prod*• ucts. However, at present, the term cytokine is widely used
to define polypeptidic factors released by practically any
type of cells. More than 50 cytokines have been described and
the majority have been cloned. Most of them have pleiotropic
effects, and some act together synergistically or are capable
of inducing or inhibiting the production of other cytokines.
»• Many of these factors are produced by immunological cells.
The immune-derived cytokines mentioned in this review are
those that can be considered as mediators of immune-neuroendocrine interactions because they exert some neuro-endocrine effect or their receptors are present in neuro-endocrine
tissues. These cytokines are listed in Table 1, together with
v their currently used abbreviation. Their main immunological
actions are also briefly summarized.
II. Reciprocal Effects Between Immune and NeuroEndocrine Mechanisms
As schematically represented in Fig. 1, the evidence that
immune and neuro-endocrine mechanisms can affect each
other has been classified as follows: A) Immune, endocrine,
or neural cells can express receptors for cytokines, hormones,
neurotransmitters, and neuropeptides; B) Immune and
neuro-endocrine products coexist in lymphoid, endocrine,
and neural tissue; C) Endocrine and neural mediators can
affect the immune system; and D) Immune mediators can
affect endocrine and neural structures.
65
A. Receptors for cytokines, hormones, neurotransmitters,
and neuropeptides in immune, endocrine, and neural cells
Reciprocal expression of receptors for products of the
nervous and endocrine system, as well as for the immune
system, constitute the basis of immune-neuro-endocrine
interactions. The presence of receptors for hormones, neurotransmitters, and neuropeptides on immunological cells
has been clearly established, and only a few classic works will
be mentioned below. However, more recent studies on the
presence of receptors for immune-derived messengers on
endocrine and neural cells will be reviewed in more detail.
1. Receptors for hormones, neurotransmitters, and neuropeptides
in immune cells. Immune cells can bind different hormones,
neurotransmitters, and neuropeptides. For example, receptors for corticosteroids (1,2), insulin (3,4), PRL (5,6), GH (7),
estradiol (8), testosterone (9), j3-adrenergic agents (10-14),
acetylcholine (15,16), endorphins (17), enkephalins (18), substance P (SP), somatostatin (SOM), and vasointestinal peptide (VIP) (19-21) have been demonstrated in lymphoid or
accessory cells. There is still some controversy regarding the
presence or the number of certain of these receptors on immunological cells. However, for the purpose of this review,
we consider it more important to discuss two aspects that are
relevant for the final effect of neuro-endocrine agents on
immune cells.
First, receptors for neuro-endocrine ligands are not equally
expressed on all types of immune cells. For example, B lymphocytes express more j3-adrenergic receptors than T lymphocytes, while CD8+ lymphocytes (cy to toxic T cells) express fewer receptors than CD4+ cells (helper T cells) (13).
This indicates that signals mediated by hormones, neurotransmitters, and neuropeptides can preferentially target,
and therefore influence, different types of immune responses. Second, the number or the activity of receptors for
a given neuro-endocrine agent may change during the activation of the cell. For example, resting lymphocytes have no
detectable receptors for insulin, but they appear after stimulation with mitogens or allogeneic antigens (3, 4). After
stimulation of quiescent cytotoxic T lymphocytes by interleukin-2 (IL-2), there is an increase in j3-adrenergic receptor
activity (22). The number of muscarinic receptors on human
leukocytes and rat T lymphocytes also increases when these
cells are activated by mitogens and allogeneic antigens or
during skin graft rejection (23). Thus, it is expected that
signals mediated by these hormones or neurotransmitters
will be predominantly perceived by cells that have been
activated by an antigen.
In summary, the presence of receptors for hormones, neurotransmitters, and neuropeptides on immune cells is an
absolute requirement for neuro-endocrine agents to exert an
effect. However, as clearly established for glucocorticoids
(24), the magnitude of the effect of a given ligand does not
necessarily correlate with the number of receptors present on
the target cell. Thus, the identification of receptors should be
taken only as an indication that immune cells can perceive
and respond to messengers present in their natural environment. As will be discussed later, several other factors, such
as the different degree of sensitivity of the various steps of
BESEDOVSKY AND DEL REY
66
Vol. 17, No. 1
TABLE 1. Cytokines that can mediate immune-neuro-endocrine interactions
Abbreviation
Name
Major immune action
IL-la, IL-1/3
Interleukin-1 a; Interleukin-1/3
Differentiation and function of cells involved in
inflammatory and immune responses; T T helper cells
to produce and secret IL-2 and the expression of IL-2
receptors; f B cell proliferation and production of Ig, f
proliferation and activation of NK cells
IL-lra
Interleukin-1 receptor antagonist
I IL-1 activities
IL-2
IL-3
Interleukin-2
Interleukin-3
1 T cell proliferation and differentiation, f NK
activity, promotes proliferation of B cells and Ig
secretion synergizes with specific factors to stimulate
production and differentiation of macrophages (and
other blood cells)
IL-4
Interleukin-4
Induces differentiation into T helper cells, proliferation
and differentiation of B cells, diverse effects on T cells
and monocytes
IL-6
Interleukin-6
Induces growth and differentiation of T cells and B cells,
activates hematopoietic progenitor cells
IL-8
IL-12
Interleukin-8
Interleukin-12
Induces chemotactic activity for T cells
. Induces differentiation of T helper cells, f growth and
activity of T and NK cells
IFN 7
Interferon-y
TNFa
Tumor necrosis factor-a
TGF/3
Transforming growth factor-j3
M-CSF
Macrophage-Colony stimulating
factor
I Macrophage activity, regulates specific immune
responses
Wide immunological effects through induction of other
growth factors and cytokines; immunostimulant and
mediator of inflammatory response
i Growth of many cells, NK activity and T and B cell
proliferation; with IL-4 f IgA secretion
I Various functions of monocytes and macrophages,
promotes growth and development of macrophage
colonies
G-CSF
GM-CSF
Granulocyte-colony stimulating
Granulocyte and macrophage co
stimulating factor
I Production of neutrophil and macrophage colonies
Promotes growth and differentiation of multipotential
progenitor cells, f all cells in the granulocyte,
macrophage and eosinophil lineage
SCF
Stem cell factor
Synergizes with various growth factors to f myeloid,
erythroid and lymphoid progenitors
The cytokines listed above are produced, although not exclusively, by immunological cells. Only those that, at present, can be considered
as mediators of immune-neuro-endocrine interactions because they exert some neuro-endocrine effect or their receptors are present in
neuro-endocrine tissues, are included. NK, Natural killer cells; Ig, immunoglobulins; f » stimulate; | , inhibit.
an immune response and the presence of other agents, will
influence the final effect of a given ligand.
2. Receptors for immune cytokines in endocrine glands. Comple-
mentary to the studies mentioned above is the identification
of receptors for immune-derived products in endocrine
glands. These studies are, in general, more recent than those
mentioned in the previous section. Although valuable evidence showing the existence of receptors for cytokines on
endocrine tissue has been obtained from normal and tumor
cell lines, we have chosen studies using normal tissues to
illustrate this point. A summary of several of the reports
available is given in Table 2, where receptors for interleukins
on the pituitary, adrenal, thyroid, pancreas, testis, and ovary
are mentioned with the corresponding bibliographic reference (25-39). The table does not indicate whether the methodology used in a given report has resulted in the characterization of a receptor or on the identification of a specific
binding site.
As can be seen in Table 2, most reports deal with receptors
for IL-1. As a whole, receptors for IL-la and j3, or the corresponding messenger RNA (mRNA), have been identified
in rat and mouse pituitary, mainly located in the adenohypophysis. Receptors or binding sites for IL-6 and IL-2 have
also been found in the pituitary. IL-1 receptors have not been
found in the adrenals (28, 40), although a recent report suggests that they might be present in bovine adrenal medullary
cells (41). There are a few reports showing that IL-1 receptors,
or the corresponding mRNA, are also present on thyroid
cells, in the endocrine pancreas, and in certain regions or
specific cells of the ovary and of the testis.
3. Receptors for immune cytokines in the nervous system. After the
finding that exogenous administration of certain cytokines
could induce pronounced endocrine changes known to be
under neural control (for references see Section D), a large
number of reports became available showing that receptors
for some of these cytokines can, in fact, be demonstrated in
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
67
Immune and neuro-endocrlne mechanisms can affect each other
Immuno orgon/llaauo
1CYH
NTNP
Endocrine gland
FIG. 1. Schematic representation of how immune and neuro-endocrine mechanisms can affect each other: A, Immune, endocrine, or neural
cells can express receptors for cytokines, hormones, neurotransmitters, and neuropeptides. B,
Immune and neuro-endocrine products coexist in
lymphoid, endocrine, and neural tissue. C, Effects
of neuro-endocrine agents on immune mechanisms. D, Effects of immune-derived products on
neuro-endocrine mechanisms. CY, cytokine; H,
hormone; NT, neurotransmitter; NP, neuropeptide.
0. EFFECTS OF IMMUNE-DERIVED PRODUCTS
C. EFFECTS OF NEURO-€NDOCRINE AGENTS
tntarmadiata matabollsm
Signal trantductlon
Selection
Radrculation
Traffic
Cytokln**
Call interactions
Anllgan praaantatlon
Effactor ntachaniBins
Autoragulatory procatMa
Naurotranamillar
Nauropaplide
Endocrina Gland
Naurotrantmlllara
Nauropaplldaa
Nauronal activity
Nauronal growth,
diftarantlatlon and
rapair
Thannoragutatlon
Food inlaka
Slaap
Bahavlor
the CNS. Different techniques such as autoradiography, immunoautoradiography, in situ histochemistry, and in situ
hybridization histochemistry (at times combined with reverse transcriptase-polymerase chain reaction), have been
used. As a whole, the existing evidence indicates the presence in the brain of receptors, or of the corresponding mRNA,
for IL-1 a and j3, IL-2, IL-4, IL-6, tumor necrosis factor-a
(TNFa), interferon-y (IFNy), macrophage-colony stimulating factor (M-CSF), and stem cell factor (SCF), either under
basal conditions or after induction (25, 26, 28, 32, 42-62).
Probably the most studied receptors are those for IL-1.
Although not all studies completely agree on the localization
of these receptors in the brain, there is a general consensus
that, in adult mice and rats, IL-1 receptors are mainly concentrated in the dentate gyrus of the hippocampus. Some
authors have found that these receptors are present constitutively, while others have detected them after endotoxin
administration. More recently, the problem of the modulation of IL-1 receptors in the brain by glucocorticoids or adrenalectomy has been addressed. Table 3 summarizes most of
the studies that have reported the presence of receptors for
different cytokines in brain tissue. Studies on the presence of
receptors on isolated brain cells have not been included.
B. Immune and neuro-endocrine products coexist in
lymphoid, endocrine, and neural tissues
Clearly, for exerting reciprocal immune-neuro-endocrine
effects, hormones, neurotransmitters, and neuropeptides
must reach immune cells, and conversely, neuro-endocrine
structures need to become exposed to products of activated
immune cells.
1. Neuro-endocrine agents in lymphoid organs. In their physio-
logical environment, immunological cells are exposed to
agents extrinsic to the immune system such as hormones,
neurotransmitters, and neuropeptides. In addition to being
exposed to hormones, immunological organs are innervated
(63-65). For example, peri vascular plexuses within the
splenic white pulp send single noradrenergic fibers between
surrounding lymphocytes, and some of these nerves come in
very close contact with immunological cells (65, 66). Also,
BESEDOVSKY AND DEL REY
68
a. Cytokines in the endocrine system. Immune-derived prod-
TABLE 2. Receptors for cytokines in endocrine glands
Receptor for"
Species
Reference
Rat
Mouse
Mouse
Mouse
Mouse
Mouse
Pig
Human
Mouse
Human
Mouse
Mouse
Mouse
25
26
27
28
29
29
30
31
32
33
34
27
35
Pituitary
Anterior pituitary'1
Exocrine pancreas
Mouse
Rat
Rat
36
37
38
Anterior pituitary
Rat
39
Endocrine tissue/gland
IL-lo
IL-1 a and /3
IL-1 (I)
IL-1 (I)
IL-1 (I)
IL-1 (II)ft
IL-1/3
IL-la
IL-1 (I)6
IL-1 (I)6
IL-1 (I)
IL-1 (I)
IL-1 (I)6
Pituitary
Pituitary
Anterior pituitary
Anterior pituitary
Anterior pituitary
Anterior pituitary
Thyroid
Thyroid0
Endocrine pancreas
Ovary**
Ovary6
IL-2 (a-chain)
IL-2
IL-2
IL-6
Testi/
Testis^
Vol. 17, No. 1
° As used here, does not distinguish receptor from binding site.
6
Indicates detection of transcripts for corresponding receptor; (I),
(II) indicates receptor type.
c
Secondary cultures.
d
Transcripts found in whole ovaries and follicular aspirates.
e
In theca-interstitial layer of growing follicles, cytoplasma and
plasma membrane of oocyte, in granulosa cells, in granulosa-luteal
cells of the corpus luteum.
^In epididymis and interstitial area of the testis.
8
In interstitial cells, cytoplasm of the epithelium of epididymal
ducts.
h
IL-2 receptors are colocalized with ACTH-positive cells.
fibers from primary sensory neurons can contact accessory
cells and probably T cells at sites of inflammation and elsewhere (67).
Immune cells can be exposed to hormones and neuropeptides produced by immune cells themselves. There is evidence that POMC-derived peptides, such as ACTH and /3-endorphins, can be produced by immunological cells. This was
first demonstrated by the detection of ACTH-like immunoreactivity in leukocytes (68). However, it is still controversial
whether this peptide is identical to ACTH of pituitary origin,
whether it is inducible by CRH, and whether it is released (69,
70). It has been reported that lymphocyte-derived ACTH is
insufficient to stimulate the adrenal gland in hypophysectomized mice (71) and rats (72). This is in agreement with the
finding that its production is very low (72) and restricted to
certain subpopulations of immune cells (73). GH and PRL
have also been reported to be produced by immune cells (74,
75). As we shall discuss later, hypophysectomy results in a
profound immunodeficiency. Thus, pituitary-like hormones
of immune cell origin are not enough to compensate for the
effects that pituitary-derived hormones exert on immune
cells. The fact that these lymphocyte-derived peptides are
produced by distinct subpopulations of immune cells (70,73)
suggests that they may play a role in immunoregulation by
exerting paracrine/autocrine actions. The same considerations may apply to neuropeptides such as VIP (76) and SP
(77) that are produced by eosinophils and mast cells, in
addition to being present in the innervation of immune
tissues.
2. Immune cytokines in endocrine and nervous systems.
ucts may influence endocrine structures as humoral signals.
However, it has also been found that some cytokines, either
constitutively or after induction, are present in endocrine
glands. Probably the best studied cytokine in this respect is
IL-6. Mouse or rat anterior pituitary cells secrete IL-6 spontaneously (78-81). Increased production is induced, either in
vivo or in vitro, by lipopolysaccharide (LPS) (80-86), phorbol
myristate acetate (81), IL-1/3 (79, 82, 87, 88), TNF (87, 89),
pituitary adenylate cyclase activating polypeptide (90), calcitonin gene-related peptide (90), IFNy (87), and prostaglandin E2 (82). cAMP-dependent (90) and -independent (82,
90) signal transduction pathways seem to be involved in
these effects. IL-6 release is inhibited by glucocorticoids (82,
84, 91, 92). As determined by Northern blot analysis, the
predominant form of IL-6 mRNA found in the pituitary after
either intraperitoneal or intracerebroventricular administration of LPS seems to be different from that found in the spleen
under the same circumstances (86). The presence of folliculostellate cells is essential for IL-6 production (78). Some authors have shown that, basally, the anterior and posterior
pituitaries release larger amounts of bioactive IL-6 than the
medial basal hypothalamus or the parietal cortex, but that the
induction of the release of this cytokine by endotoxin occurs
only in the anterior pituitary and hypothalamus (80). Other
authors have reported that most of the IL-6-containing cells
from freshly isolated mouse pituitary are positive for S-100.
In contrast, neither immunoreactive nor bioactive IL-6 was
found in AtT-20 cells (93). Recently, it was found that cells
from the neurointermediate pituitary lobe can also secrete
IL-6, and that LPS and IL-1/3 stimulate its release and the
accumulation of IL-6 mRNA in these cells (94). Vasopressin
and oxytocin inhibit the release of IL-6 induced by IL-1/3 and
LPS from cells of the neurointermediate lobe without affecting its release from anterior pituitary cells (94).
Immunoreactive IL-1/3 has been localized in the cytoplasmic granules in anterior pituitary endocrine cells and
colocalized with TSH in thyrotropes. LPS induces a
marked increase in anterior pituitary IL-1/3 message (95).
Also, constitutive expression of TNFa mRNA and its induction by peripheral injection of LPS was demonstrated
in the pituitary (96). An IL-8-like neutrophil chemoattractant is also found in rat normal anterior pituitary gland,
and it can be further induced by TNFa in a dose-dependent
manner (97).
Regarding the presence or induced expression of cytokines in the adrenal gland, IL-1-like immunoreactivity was
demonstrated in noradrenergic chromaffin cells (98). Since
these cells are of neuronal type, these results are discussed
in the following section. IL-6 is produced by adrenal zona
glomerulosa cells; its release is stimulated by several secretagogues, including IL-la and /3, angiotensin II, and ACTH
(99). The maximal release from zona glomerulosa cells is
more than 10-fold greater than that from zona fasciculata/
reticularis cells. Dexamethasone, an inhibitor of IL-6 production in several tissues, has no effect on either basal or
stimulated IL-6 production in the adrenal (99). Measurable
levels of TNFa were found in about 50% of human fetal
adrenals, but in none of the adult adrenals studied (100).
We have not been able to find reports on the presence of
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
69
TABLE 3. Receptors for cytokines in the brain
Receptor for"
Species
IL-1
Rat
IL-1
IL-1/3
IL-la
IL-la and /3
Rat
Rat
Mouse
Mouse
IL-1 6
Mouse
Localization
Modulation
Ref.
IL-1 (I)
IL-1 (I)6
Mouse
Mouse
IL-1/3
IL-1
IL-1 (I)6
IL-1
IL-1
IL-1 (I, II)
and6
Mouse
Mouse
Mouse
Mouse
Widespread, specially dense areas: dentate gyrus (granule cell layer),
pyramidal cell layer of Hip; granule cell layer of Cer, Hy
Almost all neurons
Hy, Cx
Discrete areas
High concentration: dentate gyrus (granule cells), choroid plexus
meninges; low concentrations: Cx
Intense signal: dentate gyrus (granule cells) weak to moderate signal:
pyramidal cell layer of the hilus, CA3 region
Dentate gyrus
Intense signal: dentate gyrus (granule cell layer), midline raphe system,
choroid plexus, endothelial cells of postcapillary venules weak to
moderate signal: pyramidal cell layer of hilus and CA3 region of Hip,
anterodorsal thalamic nucleus, Purkinje cells of cerebellar Cx, scattered
clusters over the median eminence
Hy, Hip
Dentate gyrus, choroid plexus
B
Hip (dentate gyrus) neurons of Hip
Humai
Normal astrocytes, normal brain tissue
IL-2
IL-2
IL-4
IL-6
IL-66
Rat
Rat
Mouse
Bovine
Rat
IL-66
IL-66
IL-66
Rat
Rat
Rat
Hip
Hip, molecular layer of Cx
B
Hy
CA1-CA4 regions, dentate gyrus of Hip habenulae, dorsomedial and
ventromedial Hy, internal capsule, optic tract and piriform Cx
Hy
Highest levels in Hip
Pyramidal neurons, granular neurons of Hip, neurons of habenular
nucleus, dorsomedial and ventromedial Hy, in piriform Cx, in scattered
neurons of Cx in granular cells of Cer, in medial preoptic nucleus and
lateral ventricle
TNFa
TNFa
p75 TNF
p55 TNF
Mouse
Mouse
Human
Greatest in BS, less in Cer, also detected in Cx, Thl and basal ganglia
Weak binding, entire B
Normal astrocytes, normal brain tissue
60
61
51
IFN7
M-CSF6
M-CSF and 6
SCF and 6
Human
Mouse
Human
Human
Normal astrocytes, normal brain tissue
B
Normal astrocytes, normal brain tissue
Normal astrocytes, normal brain tissue
51
62
51
51
6
42
43
44
25
26
45
32
28
c
d
e
f
46
47
48
49
50
51
52
53
54
55
56
8
h
57
58
59
Hy, hypothalamus; Hip, hippocampus; Cer, cerebellum; Cx, Cortex; BS, brain stem; Thl, thalamus; B, brain (region not specified).
As used here, does not distinguish receptor from binding site.
6
Indicates detection of mRNA for corresponding receptor; (I), (II) indicates receptor type.
c
Expression influenced following two injections of LPS.
d
Modulated by LPS, effect of macrophage depletion.
c
Modulated by LPS.
^Effects of LPS, glucocorticoids and adrenalectomy.
* Differential expression during postnatal development.
h
Different expression patterns during development.
1
Studied during development.
a
cytokines on the thyroid under conditions that do not involve
autoimmune processes affecting this gland. In the pancreas,
it has been shown that islet cells from normal mice can
express TNFa mRNA if cultured in the presence of IL-1/3
(101).
In the gonads, it has been found that the testis contains
large amounts of IL-1 (102). IL-1 bioactivity was found in
testicular interstitial fluid and cytosolic preparations (103,
104). It has been shown that the cytokine is produced by
Sertoli cells (105,106) and that in vivo treatment of rats with
LHs and CG induces IL-1/3 mRNA accumulation in purified
Leydig cells (107). Small quantities of bioactive TNFa were
detected in conditioned medium from round spermatid fractions, and TNF mRNA is found in both pachytene spermatocyte and round spermatid fractions where it was also detected by in situ hybridization (108). The production of TNFa
bioactivity by testicular macrophages has been demonstrated, while medium from cultured Sertoli cells, Leydig
cells, and peritubular cells appear devoid of such activity
(109). However, the bioactivity observed by assaying testicular interstitial fluid obtained in vivo could not be neutralized
by antibodies to TNF (110). In vitro, it seems that the main
70
BESEDOVSKY AND DEL REY
source of LPS-induced TNFa is testicular interstitial macrophages (111).
While some authors have not found IL-1-like bioactivity in
the ovary (102), others have reported that, after LPS injection
into mice, mRNA for IL-la and j3 is found in the ovary and
uterus (112). After pharmacological induction of follicular
maturation and ovulation, and formation of the corpus luteum in vivo, it was found that IL-lj3 mRNA is localized in
theca interstitial cells (113). In patients pretreated with GnRH
analogs, IL-1 bioactivity was found in granulosa and cumulus cell cultures and in follicular fluid (114), and mRNA was
detected in preovulatory follicular aspirates (33). Interestingly, it was found that IL-1 in human ovarian cells and in
peripheral blood monocytes increases during the luteal
phase (115). In the mouse, IL-la and /3 immunoreactivity was
found to be confined to the theca-interstitial layer of growing
follicles and during ovulation, while during luteinization,
granulosa-luteal cells of the corpus luteum demonstrated
strong staining (34). Cultured human ovarian surface epithelium secrete bioactive IL-1, IL-6, CSF-1, G-CSF, and some
GM-CSF, while no IL-2, IL-3, or IL-4 was detected (116). By
in situ hybridization, transient expression of IL-6 mRNA was
demonstrated in gonadotropin-primed hyperstimulated
ovaries, with maximal mRNA levels coinciding with the
period of formation of a capillary network around follicles
(117). Other authors have shown that the rat ovary produces
IL-6, GM-CSF, TNFa, and IL-1 before and during the ovulatory process (118). Immunoreactive TNFa was observed in
granulosa cells of healthy antral and atretic follicles and
appeared to be secreted by the granulosa cells (119). Immunoreactive and bioactive TNFa is present in the follicular
fluid of women undergoing GnRH and CG treatment to
stimulate their sexual cycles (120). TNFa mRNA was detected in rat ovary (121). In the mouse, TNFa mRNA and
protein was observed in oocytes of healthy follicles (122).
Vol. 17, No. 1
nist, IL-2, IL-3, IL-6, IL-8, IL-12, and IFN7 have been found
to be constitutively present in the CNS. The results are more
controversial regarding the constitutive expression of TNFa.
Moreover, although all reports agree that LPS administration
results in further expression of IL-1 in the brain, not all of
them indicate that it occurs in the same region. At least part
of these discrepancies could be explained by the diverse
methodology used, which ranges from immunocytochemistry or in situ hybridization to measurements of cytokine
bioactivity or concentration, or expression of the corresponding mRNA, and/or by the different sensitivity of the methods. Furthermore, in reports dealing with cytokine induction
in the brain, the doses of LPS administered are rather high.
This is particularly relevant because this cytokine inducer
can disturb the blood-brain barrier (163). In addition, the
possible contribution of endothelial cells or of the blood as ^
source of cytokines in the brain has in general not been
excluded.
In summary, certain cytokines, either constitutively or after induction, are present in the brain. The precise localization or compartmentalization of these cytokines, and
whether more physiological stimuli than those used so far 4
result in their increased central production, need still to be
clarified.
Cytokines in the peripheral nervous system: Regarding the
presence of cytokines in peripheral neural tissue, it has been
reported that IFN7-like immunoreactivity is present in nerve
terminal-like profiles in spinal cord and in a subpopulation
of primary sensory ganglion cells (159). Such immunoreactivity was also found in small sensory neurons in dorsal root
ganglia and in postsynaptic neurons of the sympathetic and
parasympathetic nervous system (164). However, it was later
concluded that the neuronal IFNy-like immunoreactive material is clearly distinct from lymphocyte-derived IFN7 (165).
IL-1-like immunoreactivity was demonstrated in noradrenergic chromaffin cells of rat and mouse adrenal gland
b. Cytokines in the nervous system.
Cytokines in the brain: Astrocytes and microglial cells were (98). This IL-1 was shown to be biologically active. Reserpine, *
which is known to deplete catecholamines, caused release of
the brain cells that were first shown to produce several cythe IL-1-like immunoreactive material (98). mRNA content of
tokines (123; for review see Ref. 124). More recently, it has
IL-la in the adrenal gland is increased by systemic adminbeen reported that certain neurons can also produce cytokines such as IL-1 (see below). We have chosen here to review istration of cholinergic agonists, but the levels of IL-la probriefly those studies that deal not with in vitro production of tein are reduced. LPS is able to induce the expression of IL-la
mRNA and protein in the adrenal gland (166). Immunorecytokines by isolated neural cells, but rather those investiactive IL-1 and IL-1 mRNA have been found in cultured
gating their presence or induction in nervous tissue. The
sympathetic ganglia (167).
summary that follows also does not include any detailed
discussion of the induction of cytokines during encephalopathies, such as those caused by brain infections. Although
such studies are, of course, vital for understanding the imC. Hormones, neurotransmitters, and neuropeptides can
portance of cytokines for brain pathophysiology, it is usually
affect the immune system
difficult to determine whether, under these circumstances,
A
cytokines in the brain are produced by resident cells or are
Studies concerning neuro-endocrine effects on immune
derived from invading peripheral immunocompetent cells.
functions were performed as early as at the beginning of this
Furthermore, in most cases, it is not clear whether locally
century. Thus, a comprehensive review of the available ininduced immune cytokines contribute to the regulation of the
formation is impossible here. Therefore, we shall provide
immune response in the CNS by affecting neural mechaonly a general overview and some examples from our own
nisms.
laboratory. However, to provide an understanding of the
Most of the reports on the presence of cytokines in the
contribution of hormones, neurotransmitters, and neuropep- ~i
nervous system refer to the brain (46,52,53,57,58,62,83,84,
tides to immunoregulation, we will provide a more thorough
96, 125-162). Table 4 attempts to summarize these reports.
discussion on the levels at which an immune response could
Several cytokines, such as IL-1, its natural receptor antagobe under neuro-endocrine control.
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
71
TABLE 4. Constitutive or induced expression of cytokines in the brain
Cytokine
Species
Region
Detected by
C/I
Ref.
Bioassay, ISH
c/
125
Northern
IHC
/I: convulsants
C/
126
127
Northern
ISH; RT-PCR
Northern
Bioassay
IHC
/I: methamphetamine
C/I: LPS-IFN
/I: immobilization stress
Transient, during ontogeny
/I: endotoxin
128
129
130
131
132
Northern
EIMA
Bioassay
ISH
RT-PCR
IRMA
PCR
ELISA
PCR
IHC
IHC
RIA
IHC
Bioassay
IHC
/I: transient ischemia
/I: endotoxin
/I: LPS icv, ip
C/I: f kainic acid
/I: f kainic acid
C/I: t LPS
C(-)/I: LPS
C/I: 2 x LPS
C(-)/I: LPS
C(-)/I: hippocampal lesion
/I: endotoxin
/I: LPS
C/
C(-)/I: endotoxin icv
C/
133
134
135
136
137
138
139
46
139
140
141
142
143
144
145
PVN, Hip, Cer
Hip, Str, Cx
Median eminence
Arcuate nucleus
Hip, Cx, septum
ISH, HC
IHC
IAR
C/
c/
c/
146
52
53
Mouse
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Mouse
Rat
Mouse
Discrete areas Cer
CSF
Hip, Hy, Cer
Hy
Anterior Hy
Hip, Str, Cer, neocortex
Facial nucleus
Cx, Hip, Thl, Hy
B
PVN, Hip
B
IHC/Northern
Bioassay
ISH, Northern
RT-PCR
Bioassay
RT-PCR
ISH
RT-PCR
Northern
ISH, Northern
Northern
/I: LPS
C/ no induction by LPS
C/
/I: LPS through IL-1
During development
/I: axotomy facial nerve
/I: kainic acid
During development
C/
C/
Rat
Rat
Rat
Rat
Mouse
Mouse
Mouse
CSF
Cx, Hip, Hy, Str
CSF
Hy
Str, Thl, Cx, Hip
B
Neurons of Hy
Bed nucleus stria terminalis, in
caudal raphe nuclei, along
ventral pontine and medullary
surface
B, neural tube, peripheral
mixed spinal nerves
Brain neuroepithelium Purkinje
neurons Cer
Choroid plexus
Ependymal cells
Networks of nerve terminal-like
profiles
Bioassay
RT-PCR
Bioassay
PCR
IHC
Northern
Western
/I: LPS icv
/I: kainic acid
C(-)/I: LPS icv, aged rats
C/I: LPS
C(-)/I: hippocampal lesion
during development
a
154
137
155
96
140
151
156
Western
During development
157
Western
During development
157
IHC, ISH
IHC, ISH
IHC
/I: LPS
/I: LPS
C/
158
158
159
IL-1/3
Rat
IL-1/3
IL-1/3
Rat
Rat
IL-1/3
IL-1/3
IL-1/3
IL-1/3
IL-1/3
Rat
Rat
Rat
Rat
Rat
IL-1/3
IL-1/3
IL-1
IL-1/3
IL-1/3
IL-1/3
IL-1/3
IL-1/3
IL-la
IL-la
IL-1/3
IL-la, /3
IL-1/3
IL-1
IL-1/3
Rat
Rat
Rat
Rat
Rat
Rat
Mouse
Mouse
Mouse
Mouse
Rabbit
Rabbit
Pig
Cat
Human
IL-lra
IL-2
IL-2
Rat
Rat
Rat
IL-3
IL-6
IL-6
IL-6
IL-6
IL-6
IL-6
IL-6
IL-6
IL-8
IL-12
(p35)
TNFa
TNFa
TNFa
TNFa
TNFa
TNFa
TNFa
TNFa
Mouse
TNFa
Chicken
TNFa
TNFa
IFNy
Pig
Guinea-pig
Rat
Granule cells dentate gyrus
pyramidal cells Hip, granule
cells Cer
granule/periglomerular cells,
olfactory bulb, dispersed cells
VMH; FCx
Cx, Thl, Hy, Hip
Periventricular medial Hy, Hip
and olfactory tubercle
Hy
Forebrain
Hy
B
Meninges, choroid plexus brain
blood vessels, non-neuronal
cells in parenchyma
Cx, Hip, Str, Thl
Hy
BS, diencephalon (extracellular)
Several regions
Cx, Thl, Hip
Hy
Str, Thl
Hip, Hy
Hip
Str, Thl, Cx, Hip
OVLT
B
Hip and blood vessels
CSF from third ventricle
Hy
c/
147
148
83,84
57
149
58
150
137
151
152
153
BESEDOVSKY AND DEL REY
72
Vol. 17, No. 1
TABLE 4. Continued
Cytokine
Species
Region
Detected by
C/I
Ref.
IFNy
Rat
Facial nucleus
/I: axotomy facial nerve
160
IHC
M-CSF
Mouse
Granule cells Cer
RNase protection
C
161
M-CSF
B
Mouse
Si-analysis
From ED 13 to adulthood
62
B
CSF-1
Mouse
Northern
During development
151
TGF/32
Mouse
B
Northern
During development
151
Cx
TGF/3
Rat
Northern
C/
162
Hy, Hypothalamus; Hip, hippocampus; Cer, cerebellum; Cx, cortex; FCx, frontal cortex; CSF, cerebrospinal fluid; OVLT, organum vasculosum
lamina terminalis; BS, brain stem; PVN, paraventricular nucleus; Str, striatum; Thl, thalamus; B, brain (region not specified); ISH, in situ
hybridization; HC, histochemistry; IHC, immunohistochemistry; IAR, immunoautoradiography; Northern, Northern blot analysis; Western,
Western blot analysis; IRMA, immunoradiometric assay; EIMA, enzyme amplified immunometric assay; \ , increased; ED, embryonic day; C/,
constitutive expression; C(—), not found constitutively; I, expression induced by; icv, intracerebroventricular.
1. Endocrine effects on the immune system. Investigations into
the participation of hormones in the immune response have
generally involved either the parenteral administration of
hormones, antagonists, and blockers, or the ablation of endocrine glands. Numerous reports agree that hormone administration can lead to depressed or stimulated immune
responses, depending on the kind and dose of hormones and
the timing of their administration. In general, glucocorticoids, androgens, progesterone, and ACTH depress the immune response in vivo, whereas GH, PRL, T4, and insulin
increase the response (168-179). Gender differences in the
immune response are well documented. Females develop
stronger immune responses, have higher immunoglobulin
concentrations, and are more resistant to the induction of
immunological tolerance than males (for review see Refs. 170
and 180). Furthermore, the incidence of certain autoimmune
diseases is higher in females (181). Opioid peptides, particularly j3-endorphin and Met-enkephalin, have also been implicated as immunomodulators since they can affect several
immune mechanisms. However, it is difficult to conclude
whether, as a whole, these peptides are immunosuppressive
or immunostimulant since the effects reported differ depending on the type of immune process studied, on the cell
source and type, on the species, on the concentration of the
opioid peptide used, and on experimental conditions, i.e. in
vivo or in vitro. An analytic discussion of this subject is beyond the scope of this article (for review see Refs. 180 and
182).
Hypophysectomy suppresses hematopoiesis and immune
cell proliferation and causes atrophy of lymphoid organs and
a progressive deterioration of all immune functions (for review see Ref. 183). Immunodeficiency in hypophysectomized animals can be reversed by PRL, GH, and placental
lactogens, but not by other pituitary hormones (176, 183).
Administration of bromocriptine, which specifically blocks
PRL release, causes immunodeficiency. PRL administration
has been shown to reverse this effect. This hormone has also
been shown to stimulate immune parameters in normal animals (184).
It has been shown that PRL mRNA is expressed in mitogen-stimulated lymphocytes (74), and that addition of a specific antibody to PRL to the culture medium results in inhibition of lymphocyte proliferation (185). However, the
inhibitory effect of hypophysectomy on immune functions in
vivo cannot be counteracted by the lymphoid cell-derived
PRL. The other pituitary immunostimulatory hormone is
GH, which has been shown not only to enhance immune
responses but also to delay aging of the immune system
(186). ACTH has been reported to inhibit different immune
functions independently from its capacity to stimulate glucocorticoid output (174, 187).
The inhibitory effect of adrenocorticoid hormones in a
variety of immune and inflammatory mechanisms has resulted in their widespread therapeutic application. However,
most of the evidence derives from pharmacological studies,
and less is known about the effect on immune functions of
fluctuations of endogenous levels of glucocorticoids. For example, in animals kept under conventional conditions but
without further antigenic stimulation, we studied the relationship between endogenous glucocorticoid blood levels
and the number of splenic B lymphocytes secreting immunoglobulins at a given time (188). A clear inverse relationship
between the values of corticosterone in blood of adrenalectomized, sham-operated, and stressed mice and the number
of antibody-secreting cells in the spleen is observed. An
approximately 10- to 15-fold variation in glucocorticoid
blood levels was paralleled by oscillations of the same magnitude in the number of antibody-secreting cells (10-fold).
These data show that endogenous levels of glucocorticoids
contribute to the control of B cell activity. Since most immune
responses involve the cooperation between T and B lymphocytes, we can conclude that the pituitary-adrenal axis
affects the overall activity of the immune system.
2. Neural effects on the immune system. Data on the effects of
autonomic nervous system mediators on the immune system
are contradictory, but in the main they indicate that neurotransmitters can influence the immune response, both in vitro
and in vivo (11,16,189-194). We (195) and others (196) have
observed that neonatal sympathectomy with 6-hydroxy-dopamine enhances the immune response to several antigens.
A similar effect was also observed in adult rats after surgical
denervation of the spleen. However, adult chemical sympathectomy had the opposite effect (197-199). We recently
found that chemical denervation at birth results in increased
numbers of immunoglobulin-secreting cells in the spleen of
adult mice that were kept under conventional conditions but
did not receive further antigenic stimulation (200). Because
neonatal administration of 6-hydroxydopamine results in a
permanent destruction of sympathetic nerve endings, the
results strongly suggest that there is a permanent increase in
the activity of splenic B lymphocytes in mice deprived of
sympathetic innervation. Furthermore, these results agree
with the reported enhancing effects of sympathectomy on
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
antibody-forming cells in immunized animals. Since 6hydroxy-dopamine administered at birth not only interferes
with the sympathetic innervation of peripheral organs but
also with central noradrenergic neurons, our studies do not
allow definitive conclusions about which of these structures
affects the function of B cells. However, these studies reveal
the relevance of central and autonomic mechanisms in immunoregulation under basal and activated conditions.
Parasympathetic agents have also been reported to affect
antibody formation and cytotoxicity (194, 201, 202).
Several neuropeptides can affect immune cell activity. For
example, SP enhances B cell production of immunoglobulin
M (IgM) and immunoglobulin A (IgA), but not of IgG (203).
SOM and VIP have opposite effects on B cells and also inhibit
T cell proliferation (204). SP, SOM, and VIP stimulate mast
cells to release mediators of hypersensitivity such as histamine and platelet-activating factor (PAF) (205). SP also has
a stimulatory effect on specific immune responses (206-208).
The overall picture indicates that, in general, SP exerts stimulatory effects while VIP, SOM, and neuropeptide Y inhibit
immune functions (204, 209-211).
There is also abundant evidence showing that direct manipulation of the brain, e.g. electrolytic lesions or stimulation
of different parts of the brain, can affect the immune response
(212-216). The effects on the immune response caused by
stress (217-221) and circadian rhythms (222), and the complex phenomena of conditioning of the immune response
(223-227), also show that processes integrated at the level of
the CNS can affect immune functions.
73
growth factors. For example, during an immune response,
accessory cells must process the antigen to present it appropriately to lymphocytes, which transform into blasts and
undergo clonal expansion after receiving this information.
These and other immune processes, such as phagocytosis,
cell migration, and homing, are mechanisms involving high
metabolic demands. Since lymphocytes are the only cells that
need to proliferate to reach the mass necessary to fulfill their
specific functions, they are particularly influenced by neuroendocrine signals that control intermediate metabolism
(228).
Two main pathways, one involving cAMP and the other
inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) as
second messengers, are used by hormones, neurotransmitters, and neuropeptides for intracellular signal transduction.
There is evidence that these pathways are also used by certain cytokines, antigens, or mitogens when they bind to their
respective receptors in immune cells. For example, binding
of an antigen to its specific T cell receptor (229) or addition
of IL-2 to cell lines that depend on IL-2 for growing (230)
results in activation of phospolipase C, yielding IP3 and DAG
as intracellular second messengers. It is also clear that the T
cell antigen receptor and interleukin receptors utilize G proteins as an initial transducer to amplifier systems (230).
Whether these G proteins are unique or are also used by
hormone receptors is not known. It is beyond the scope of
this article to review this matter in detail (for review see Refs.
229-232). However, it seems likely that neuro-endocrine and
immune-mediated stimuli share mechanisms for intracellular signal transduction. The evidence in support of this pos3. Immune mechanisms that can be affected by neuro-endocrine
sibility is still very fragmentary, and much more work is still
agents. The evidence discussed above shows that hormones, needed in this particular area. Nevertheless, we wish to emneurotransmitters, and neuropeptides can affect the activity
phasize this aspect here since immune cells are probably,
of the immune system. Most of these studies evaluated the
except for neurons, the cells that are exposed to the most
influence of neuro-endocrine signals on the immune system
diversified array of signals from inside and outside the orwith respect to either the proliferation of immune cells or the
ganism. Furthermore, since immune cells are mobile, they
final effector mechanism, such as the production of antibodare also exposed to locally generated mediators in the difies or the activity of cytotoxic cells. The generation of specific
ferent microenvironements where they circulate or are loeffector cells and molecules of the immune system can be
cated. The common use of intracellular transduction signals
influenced at several levels. These levels range from very
by hormones, neurotransmitters, neuropeptides, and imgeneral processes, such as the intermediate metabolism of
mune ligands would provide a molecular basis for synerimmune cells, to more specialized mechanisms, such as the
gistic and antagonist effects of neuro-endocrine and immune
selection of cells that can recognize a huge repertoire of
agents on the immune response. In addition, the convergence
antigens, and the production of the cytokines that support
of different types of stimuli that do not share the same inlymphoid cell growth and differentiation. Furthermore, the
tracellular signaling pathway may contribute to interactions
efficiency of an immune response depends also on the conbetween immune and neuro-endocrine agents. For example,
trol of processes such as the proliferation of cells with low
stimulation of the T cell receptor results in activation of the
affinity for the antigen, the interaction between immune cells
phosphoinositide pathway without affecting the levels of
and their targets, and the mobility, migration, and homing of
cAMP. However, the increase in intracellular levels of cAMP
these cells. The following is a discussion on the effects of
induced by stimulation of /3-adrenergic receptors in lymhormones, neurotransmitters, and neuropeptides on some of
phocytes is further enhanced if the T cell receptor is also
these processes.
stimulated (229). Since an increase in intracellular cAMP
levels inhibits proliferation, this may explain the fact that
a. Intermediate metabolism and intracellular signal transduction in immune cells. The control of the metabolism of immune stimulation of /3-adrenergic receptors at the time of lymphocyte activation ultimately results in a decreased proliferative
cells and the concentration of second messengers used for
intracellular signal transduction, e.g. cAMP, can be affected response.
by neuro-endocrine signals. These mechanisms are specially
In summary, the outcome of the biochemical events inisensitive to neuro-endocrine signals due to some peculiaritiated in a lymphocyte after recognition of an antigen or
ties of immune processes.
induced by a cytokine would, in fact, depend on other intracellular signals resulting from the simultaneous binding
Immune cells are highly dependent on nutrients and
74
BESEDOVSKY AND DEL REY
Vol. 17, No. 1
dorphin and enkephalins, affect mononuclear cell mobility
of neuro-endocrine ligands that occur under physiological or
(243-247).
pathological conditions.
b. Negative and positive selection of lymphocytes during on-T and B lymphocytes express higher numbers of receptor t
togeny. During ontogeny, the precursors of T lymphocytes for neuropeptides such as SP and SOM when they are located
in lymphoid tissues than when they circulate in the blood
expressing receptors with high affinity for self-antigens are
(248, 249). It has been shown that down-regulation of VIP
eliminated (negative selection), and those with low affinity
receptors
in T lymphocytes reduces their homing in tissues;
are stimulated to become mature T cells (positive selection).
this
is
possibly
evidence for selective trapping of lymphoThis selection occurs mainly, but not exclusively (233, 234),
cytes expressing more receptors for these neuropeptides
in the thymus. Programmed cell death, or apoptosis, is a
(241, 242). It is, therefore, likely that lymphocytes are more J
process of selective cell deletion that contributes to the essensitive
to neuropeptides when they are located in regions
tablishment of tolerance to self-antigens. Stimulation of T cell
in
which
they are more exposed to these nerve mediators.
receptors in immature thymocytes leads to apoptosis. ExpoControl
of gene expression and production of cytokines and
e.
sure of these cells to glucocorticoids results in a similar phereceptors.
The production of several lymphokines and
their
nomenon. However, the induction of apoptosis is prevented
monokines,
which
are necessary for cell differentiation,
when these two events occur simultaneously. It was recently
transformation,
and
clonal expansion, and the expression of j
reported that thymic epithelial cells can produce steroids
their respective receptors can be affected by neuro-endocrine
(235). Glucocorticoids produced in the thymus are capable of
signals. Most available reports consider the glucocorticoids
antagonizing the apoptosis induced by stimulation of those
and their effects on IL-1, IL-2, IL-4, TNFa, CSF, and IFNy
T cell receptors that bind with low affinity to self-antigens in
production (250-256). All the studies mentioned, with the
the thymic epithelium. By these means, glucocorticoids
exception of the one on IL-4, show that glucocorticoids inwould favor positive selection in the thymus. This is a prohibit cytokine production. Only a few reports consider horvocative hypothesis, but one should consider that circulating
monal effects on the expression by immune cells of receptors <
steroids derived from the fetal adrenal gland may also confor lymphokines and monokines. Glucocorticoids induce extribute to both negative and positive selection (236). Other
pression of IL-1 receptors predominantly on B cells (257),
neuropeptides present in the thymus, such as oxytocin and
while dexamethasone does not affect the number and affinity
vasopressin, could contribute to the selection process and
of IL-2 receptors (258). In human monocytes, IL-6 receptor
promote thymocyte differentiation (237, 238).
mRNA levels have been shown to decrease in response to
c. Contribution to immunospecificity. The specificity of an glucocorticoids (259). With regard to effects of other horimmune response to an antigen is based on the stimulation
mones, it has been shown in monocytes that both TNF reof those lymphoid cells that possess high affinity receptors
ceptors and TNF production are decreased by insulin (260), -J
for the antigen. However, other processes that can occur
and that PRL induces IL-2 receptors on unfractionated
during an immune response may affect such specificity, e.g. splenocytes (261). There are also studies showing that certain
the binding of the antigen to cells expressing receptors with
neurotransmitters and neuropeptides influence the produclow affinity and the polyclonal stimulation of cells by certain
tion of cytokines. Noradrenaline (NA) has been shown to
cytokines. There are mechanisms by which hormones and
decrease IL-1 production (262), whereas a2-adrenergic agoneurotransmitters can contribute to make the immune renists increase TNF release by LPS-stimulated macrophages
sponse more specific. These mechanisms are based on pref(263). SOM and VIP decrease IFNy; SP and substance K 4
erential effects of these agents on either resting or activated
produce an increase in IL-1, TNF, and IL-6 release from
cells and are related to the stage of the immune response
human peripheral blood leukocytes (264, 265); and SP induring which the neuro-endocrine mediators are released.
duces an increase in IL-2 activity (266). There are few studies
Since this aspect is linked to the participation of neuro-enregarding the influence of neurotransmitters and neuropepdocrine mechanisms in immunoregulation, it will be distides on the expression of receptors for cytokines on immucussed in more detail in Section III. C.
nological cells. Adrenaline and SOM reduce receptors for ,1
d. Immune cell recirculation and homing. The circulation ofTNF on monocytes (260); /3-adrenergic agonists induce a
immune cells, as well as their traffic through and within
reduction of IL-2 receptors in lymphocytes (267); and SP
lymphoid structures and homing in tissues, is essential to
enhances IL-2 receptors in gut-associated lymphoid tissue
immunosurveillance and to an efficient immune response.
(266).
These processes can be affected by neuro-endocrine agents.
/. Immune cell interactions and autoregulatory mechanisms of
Catecholamines cause increased outflow of lymphocytes
the immune response. It is well established that T lymphocytes
and granulocytes from the spleen of normal guinea pigs
recognize an antigen when it is expressed on the surface of ^
(239). In immunized animals, adrenaline causes a selective
a cell in association with self-markers that belong to a group
release of antibody-producing cells from this organ (240).
of molecules known as the major histocompatibility complex
(MHC). For example, cytotoxic T cells recognize an antigen
Neuropeptides derived from nerve fibers in lymphoid oronly if it is presented in combination with MHC molecules
gans and in other tissues where an immune response may
of a given class (class I), and T helper cells only if it is
take place can also affect immune cell traffic and migration.
associated with class II MHC molecules. Thus, the recogni- .
VIP infusion reduces the outflow of lymphocytes in the efferent lymph of cannulated lymph nodes (241, 242). In vitro, tion of MHC markers is crucial for antigen presentation and
for an effective communication between different types of
it has also been shown that several neuropeptides such as
VIP, SP, bombesin, and arginine-vasopressin, as well as /3-en- immune cells and between immune cells and their targets.
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
There is some evidence that hormones can directly, or indirectly, influence the expression of class I and II MHC molecules in immunological cells and their targets. For example,
glucocorticoids affect cytokine-mediated expression of class
I and II MHC antigens on macrophages (254, 268, 269). Neurotransmitters and neuropeptides can also influence MHC
expression. There is evidence that noradrenaline (NA) and
VIP can inhibit the expression of class II molecules on antigen-presenting cells in the brain (270, 271).
For an efficient immune response, the quantitative relation
between different types of immune cells, for example helper
(CD4+) and cy to toxic (CD8+) T lymphocytes, must be appropriated. As mentioned before, this can be affected by
glucocorticoids and sympathetic neurotransmitters (13, 272,
273).
Regulatory interactions between antibody classes can also
be modulated by neuro-endocrine agents. The antibody
switch between IgM and IgG can be influenced by glucocorticoids (274, 275). SP stimulates the production of IgM and
IgA (203). VIP and SOM oppose this effect (276).
Idiotypes are certain regions of the antibody molecule,
close or within the antigen-combining site, that can elicit the
production of other antibodies (anti-idiotypes). Interactions
between idiotypes and anti-idiotypes form the basis of a
refined autoregulatory mechanism of the immune response
called the idiotypic network. The degree of connectivity
within this network can also be affected by neuro-endocrine
agents since, as mentioned before, the number of antibodysecreting cells in animals that were not intentionally immunized is inhibited by glucocorticoids and sympathetic neurotransmitters (188, 200).
D. Immune cell products can affect neuro-endocrine
mechanisms
From the previous discussion it is clear that hormones,
neurotransmitters, and neuropeptides can affect immune
functions. The evidence that this is reciprocated and that
immune cell products can affect neuro-endocrine mechanisms will be reviewed in this section. We approached this
question by studying whether factors released by immunological cells after in vitro stimulation were capable of inducing in vivo neuro-endocrine effects. Upon injection into normal animals, the supernatants, obtained from cultures of
allogeneic and/or mitogenic stimulated human or murine
lymphocytes, evoked an increase in ACTH and corticosterone output (277, 278). The products that mediated these
effects were generically termed glucocorticoid-increasing
factors. The fact that 1 million lymphocytes stimulated in
culture produce enough glucocorticoid-increasing factors to
induce a several fold increase in ACTH and corticosterone
levels in the blood of normal animals illustrates their potency. Later, we showed that these conditioned media were
also capable of decreasing the NA content of the hypothalamus (279).
These results fully confirmed our prediction that factors
derived from immune cells can affect neuro-endocrine mechanisms (280, 281). Later, pure or recombinant immune cytokines became available, and it was possible to test their
capacity to influence endocrine and neural functions. In the
75
following, we shall attempt to provide an overview of the
enormous bulk of information that has been published on
this matter during recent years.
1. Effects of immune-derived products on endocrine
mechanisms,
The capacity of IL-1 to stimulate the hypothalamus-pituitaryadrenal (HPA) axis is the most extensively studied example
of the influence of cytokines on endocrine functions. Both the
purified natural and the recombinant human forms of IL-1
can stimulate ACTH and corticosterone output in mice and
rats. Also, IL-1 appears as the most likely mediator of the
glucocorticoid changes induced by certain viruses (282). This
effect of IL-1 seems to be rather specific since it is not paralleled by changes in other "stress hormones," such as somatotropin, PRL, and a-MSH. The levels of catecholamines
in blood are only modestly increased after IL-1 injection
(283). As will be discussed later, although the main site of
action of IL-1 is the hypothalamus, it can also affect ACTH
released during long term cultures of normal pituitary cells.
It has also been shown that IL-6, TNFa, and IFN7 stimulate
the pituitary-adrenal axis (284-286). Another factor that increases plasma corticosterone levels in vivo is thymosin fraction 5 (287). Comparative studies on the capacities of IL-1,
IL-6, and TNFa to stimulate the pituitary-adrenal axis
showed that IL-1 is more potent than TNFa and IL-6 (288).
After this initial evidence that lymphokines and monokines can affect the pituitary-adrenal axis, further studies on
this effect and on other neuro-endocrine mechanisms have
been performed. The effect of several cytokines on the hypothalamus-pituitary axis in vivo is summarized in Table 5,
which includes some specific details (282-336). Generally,
IL-1, TNF, and IL-6 exert an inhibitory effect on the hypothalamus-pituitary-thyroid axis. Regarding the hypothalamus-pituitary-gonadal axis, it is worthwhile to mention that
IL-1 induces a decrease in LHRH and LH concentrations only
if the cytokine is administered centrally. This indicates that
the actions of IL-1 on plasma LH levels are most likely mediated within the brain (321). However, IL-1 may also affect
sexual steroid production by acting directly on the gonads
(see below). Another effect of IL-1 that is observed only when
IL-1 is injected intracerebroventricularly is an increase in PRL
and GH plasma levels.
Although these experiments are pharmacological, they
are, in our view, valuable for assessing the potential physiological neuro-endocrine effects of cytokines since they were
performed in vivo. A large number of studies have also been
performed in vitro (36, 87, 89, 337-359). These results are
summarized in Table 6. The evidence is sometimes contradictory as seen from the effects of IL-1 on ACTH and PRL
release and the effects of TNF on GH and PRL release. This
is probably due to the different in vitro systems used and to
different culture conditions. However, as a whole, the evidence indicates that IL-1, IL-2, IL-6, TNFa, and IFN7 can also
directly affect the pituitary gland.
The effect of cytokines on the adrenal (40, 100, 360-371)
gland is summarized in Table 7. The majority of these studies
derive from in vitro work since the aim was to study direct
effects of the cytokines on the adrenal. The results indicate
that IL-1, IL-2, and IL-6 can increase the release of glucocorticoids. Regarding the effect of cytokines on aldosterone se-
BESEDOVSKY AND DEL REY
76
Vol. 17, No. 1
TABLE 5. In vivo effects of cytokines on the hypothalamus-pituitary axis
Cytokine
Species
Route
Endocrine effect
ACTH, [ t corticosteronel
ACTH
ACTH, [ | corticosterone] (sex and strain dependent)
ACTH, [ | corticosterone]
CRF, t ACTH
ACTH, | CRH and T mRNA CRH (in
hypothalamus)
mRNA CRH (in PVN), f ACTH, [ | corticosterone]
mRNA POMC (in pituitary)
ACTH, [ 1 corticosterone]
ACTH
ACTH, [ 1 corticosterone]
ACTH, [ f corticosterone]
ACTH, [ f corticosterone]
ACTH (in pituitary) t CRH (in hypothalamus)
ACTH
ACTH, [ | corticosterone] (blocked by a-MSH)
ACTH, t vasopressin
ACTH, [ | corticosterone]
ACTH, [ f corticosterone]
ACTH
ACTH, [ t corticosterone]
mRNA CRF, | CRF (PVN)
ACTH, [ 1 corticosterone], age dependent
GH, t PR, I TSH
LH
TSH, [ | free T4; | T4-binding prealbumin levels I
LH-RH(ME), | LH
LH, | FSH, | PG (disruption estrous cycle)
LH, | PRL (blocked by a-MSH)
LH, | FSH, [ t cortisol] (blocked by CRH
antagonist)
PRL
Ref.
IL-1/3
IL-la
IL-la,/3
IL-1/3
IL-1/3
IL-la,/3
Mouse
Mouse
Mouse
Rat
Rat
Rat
ip
ip
ip
ip
ip
ip
|
f
f
f
t
t
IL-1/3
Rat
ip
IL-la,/3
IL-1/3
IL-1/3
IL-1/3
IL-1/3
IL-1/3
IL-la
IL-la
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Rat
iv
iv
iv
icv
IL-1/3
Rat
IL-1
IL-1/3
IL-1/3
IL-10
IL-10
IL-1/3
IL-1
IL-la,/3
IL-1/3
IL-1/3
IL-1/3
IL-la
IL-la
Rat
10-day rat
Rat
Rat
Rat
Rat (neonate)
Rat
Rat (cast)
Rat
Rat
Rat
Monkey (ov)
Monkey (ov)
icv
icv
|
f
t
t
t
t
f
t
t
f
j
f
f
t
f
f
f
f
|
4
|
I
i
i
IL-1/3
Pigeons
icv
t
IL-2
IL-2
Rat
Pigeons
ip
icv
t mRNA POMC (in pituitary)
t PRL
329
328
IL-6
IL-6
IL-6
IL-6
IL-6
IL-6
IL-6
Mouse
Rat
Rat
Rat
Rat
Rat
Rat
ip
iv
iv
iv
ip
icv
icv
t
t
f
t
f
t
t
ACTH
ACTH,
ACTH,
ACTH
ACTH,
ACTH
ACTH,
291
284
288
303
300
330
331
TNFa
TNFa
TNFa
TNFa
TNFa
Rat
Rat
Rat
Rat
Human
iv
iv
iv
icv
iv
t
t
|
t
t
ACTH, [ | corticosterone]
ACTH
TRH (in hypothalamus), 4 TSH, [T4, free T4, T3]
ACTH, t GH
LH, 1 FSH, [ | testosterone]
ip, icv
iv (r)
iv (r)
icv
iv, icv
ip minip
ip
icv
ihyppoc
icv
ip
icv
icv
ip (minip)
icv
icv (prl)
t CRH
[ f corticosterone]
[ t corticosterone]
| TSH
282, 289, 290°
291
292
293, 2946
295, 296, 297, 298
299
300
301, 302, 288
303, 304, 305c
306d
307c, 308
309/"
310
310
311
312
313
314
315
316
317*
318
319
320, 321, 322*
323
324
325
326
327
328
301, 332, 288
285, 333'
334
335
336
[] Indicates peripheral hormone evaluated in parallel. POMC, proopiomelanocortin; PVN, paraventricular nucleus; ME, median eminence;
ov, ovariectomized; cast, castrated; (r), repeated injections; prl, prolonged treatment; i hippoc, intrahippocampal; minip, minipump; | , increase;
1, no change; 1, decrease.
a
Effect inhibited by a-MSH.
6
Effect is age, gender, and sex steroid dependent.
c
Capsaicin desensitization reduces the IL-1-induced increase in plasma ACTH.
d
Effect increased by blockade of nitric oxid syntethase.
c
Effect blocked by 6-OH-DA or a-adrenergic antagonist.
f
Effect inhibited by mediobasal hypothalamic deafferentation.
8
Studies in different strains.
h
Effect blocked by naloxone.
1
Effect mediated by prostaglandins.
cretion, the results obtained in vivo and in vitro are contradictory. It has been reported that IL-1 and TNF inhibit
angiotensin- and ACTH-induced aldosterone secretion in
cultures of adrenal cells. However, we have observed that,
after intravenous administration of IL-1 to rats, a marked
increase in aldosterone blood levels is detected in parallel to
elevated levels of ACTH and PRA (304). Reports on the effect
of cytokines on the thyroid gland are summarized in Table
8 (323, 334, 372-386). The results show that IL-1 and TNFa
inhibit thyroid functions in vivo and in vitro.
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
77
TABLE 6. Effects of cytokines on the pituitary in vitro
Cytokine
System
Effect
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
IL-1
AtT-20 cells
Pituitary cell cultures
Pituitary cell cultures
Pituitary cell cultures
Pituitary cell cultures
Superfusion pituitary cells
Perifusion pituitary cells
Pituitary cell cultures
Pituitary cultures
Superfused neurohypophysis
Pituitary cells
Pituitary cells
Anterior pituitary perifusion
IL-1
Pituitary cultures
t ACTH
t ACTH, LH, GH, TSH, | PRL
t ACTH, no change in LH, GH, FSH and PRL
f ACTH, not change in LH and GH
f ACTH (only if long term cultures)
No effect on ACTH
t ACTH, LH, GH, TSH, PRL (very quick effects)
I TSH-induced PRL release
4 PRL
f Vasopressin, | oxytocin"
t PRL
4 FSH, t LH
No effect on ACTH secretion, although confirm
effect in vivo
No effect on ACTH
IL-2
Pituitary cells
t ACTH
IL-6
IL-6
IL-6
TNFa
Pituitary
Pituitary
Pituitary
Pituitary
TNFa
TNFa
TNFa
TNFa
TNFa
TNFa
TNFa
Pituitary cells
Pituitary cells
Pituitary cells
Pituitary cells
Pituitary cells
Pituitary cells
Anterior pituitary cells
t PRL
f PRL, GH and LH
No effect on ACTH
1 ACTH, PRL, and gonadotropins (not later than
30 min)
T GH
4 GH
4 CRH-induced ACTH release (long term cultures)
t PRL
No basal effect, 4 TRH-stimulated TSH secretion
t PRL
4 PRL (more pronounced if combined with IFNy)
no effect on TSH
IFN7
Pituitary cell cultures
IFNy
Anterior pituitary cells
cells
cell cultures
cultures
cells
4 Hypothalamic releasing factor-induced release of
ACTH, PRL and GH
t PRL
Ref.
337
338
339
340
341
342
343
344
345
346, 347
348
349
350
351
36
348
352
351
353
89
354
355
356
357
348
358
359
87
f , Increase; 4 , decrease.
a
Electrically evoked release.
Effects of cytokines on the endocrine pancreas in vivo are
difficult to evaluate because of the profound metabolic action
of some of these mediators (see Section D.3.). The results from
in vitro experiments are controversial. It has been reported
that IL-1 can either stimulate or inhibit insulin release by
isolated rat islets depending on the dose used (387, 388).
Using isolated perfused pancreas, it has also been found that
IL-1 increases insulin release in response to glucose (389,390)
and stimulates glucagon secretion irrespective of increasing
glucose and insulin concentrations (390). Glucose-induced
insulin secretion was potentiated in pancreases obtained
from rats after in vivo administration of IL-1 (391), while
glucagon secretion in response to an arginine stimulus was
not affected (392). In contrast, other authors have reported
that IL-1, TNFa, and IFN7 inhibit both j3- and a-cell-secretory
functions in islet monolayers, while only IL-1 and TNF produced sustained decreases in insulin and glucagon content
in islet cultures (393). In isolated human islets, IL-1, TNF, and
IL-6 inhibit insulin release in response to high doses of glucose and almost completely block basal glucagon release
(394). However, a proper evaluation of these results must
consider that some of these cytokines can be cytotoxic in vitro
(393, 395).
Effects of IL-1, IL-2, and TNF on testis and ovary have also
been studied. In vitro, IL-1 stimulates progesterone release
(396,397), while TNF exerts an opposite effect (398,399). IL-1
and TNF inhibit gonadotropin-induced estradiol production
(114, 400). IL-1 (401) and IL-2 (402) inhibit gonadotropininduced testosterone synthesis. Other authors have reported
that IL-2 and IFNy decrease LH-induced testosterone production in isolated Leydig cells, but IL-2 increases testosterone production in minced murine testis (403). TNF stimulates
testosterone secretion in vitro (404) but inhibits the production of this hormone in vivo (336, 405). Interestingly, it has
been recently shown that conditioned medium from macrophage cultures inhibit testosterone production by Leydig
cells in vitro (406, 407).
In this section, we often referred to effects of cytokines on
endocrine glands in culture. These studies were performed
to obtain evidence for direct effects of these mediators on
hormone production. However, it is necessary to consider
that cytokine actions are primarily exerted in a paracrine
fashion, and that these mediators can act as growth factors
and nonspecifically influence cell metabolism. Thus, some of
the effects described cannot be interpreted as "endocrine
actions" of cytokines since they might reflect effects that
occur when they are locally produced in the tissues (for
example, during inflammatory and autoimmune processes).
In contrast, the data obtained in vivo clearly show that certain
Vol. 17, No. 1
BESEDOVSKY AND DEL REY
78
TABLE 7. Effects of cytokines on the adrenal gland
Cytokine
System
Effect
Ref.
IL-1 a,/3
IL-1
IL-10
IL-1
IL-1
IL-1/3
IL-1
IL-1/3
IL-1
IL-la
Quartered adrenal, dispersed cell cultures
Human adrenal cell and organ culture
In situ perfusion
Human adrenal cells
Bovine adrenal cells
Adrenal slices
Rat adrenal cells
Isolated zona glomerulosa, capsular strips
Chromaffin cells
Adrenal cells
360
361
362
363
40
364
365
366
367
368
IL-1/3
Glomerulosa cells
| Corticosterone
No effect on cortisol
f Corticosterone (mediated by PG)
f Cortisol (more effect with monocyte supernatant)
f Cortisol (mediated by PG)
f Corticosterone
f Corticosterone (mediated by PG)
I Angiotensin-induced aldosterone secretion
t VIP, 4 Met-enkephaline
I Epinephrine, f corticosterone (a-adrenergic
mediated, not mediated by PG)
4 Angiotensin-induced aldosterone secretion
IL-2
Rat adrenal cells
| Corticosterone (mediated by PG) (effect only
with rat IL-2, not with human IL-2)
365
IL-6
IL-6
Adrenal cultures
Rat adrenal cells
t Corticosterone
f Corticosterone (mediated by PG)
370
365
TNFa
TNFa
TNFa
TNFa
IFN 7
Chromaffin cells
Human fetal adrenal
Glomerulosa cells
Human fetal adrenal
Human fetal adrenal
f
f
4
4
I
367
371
369
100
371
VIP, | Met-enkephaline
mRNA insulin-like growth factor II
Angiotensin and ACTH-induced aldosterone
Cortisol, shift to androgen production
mRNA insulin-like growth factor II
369
PG, Prostaglandin; f , increase; 4 , decrease.
cytokines can serve as mediators in the bidirectional communication between the immune and endocrine systems.
Apart from cytokines, other potential immunological messengers capable of influencing neuro-endocrine processes
are histamine, serotonin, and serotonin precursors, which are
released during certain immune responses (10); the pituitary
hormone-like peptides that are produced by stimulated lymphoid cells (68,408,409); and thymic hormones, vasopressin,
and oxytocin, which can be produced by thymic nurse cells
(238, 410). Antibodies can also be candidates for mediating
immune-neuro-endocrine interactions since the Fc part of
immunoglobulins has been shown to bind to pituitary
ACTH-producing cells (411). Even specific antibodies can
affect the endocrine systems. For example, antihormone antibodies can share common characteristics with hormone
receptors, and the anti-idiotypic antibody may act as the
ligand, thereby behaving as an internal "image" of the hormone. This mechanism could explain the appearance of autoantihormone antibodies and antihormone-receptor antibodies during different autoimmune diseases (412, 413).
Antibodies have also been shown to modify hormonal action,
e.g. by changing the affinity of the hormone for the carrier,
by protecting hormones from enzymatic degradation, and by
stabilizing particular conformations in the molecule (414).
2. Effects of immune-derived products on the nervous system. The
effects exerted by lymphokines and monokines on neuroendocrine mechanisms imply that these products can directly or indirectly affect neural functions.
a. Effect of cytokines on the production ofhypothalamic releasing
factors. The first hypothalamic releasing factor whose production was shown to be affected by a cytokine was CRH
(295-297). IL-1, whether administered systemically or intracerebroventricularly or applied in vitro (415, 416), stimulates
CRH production in the hypothalamus. This finding and
other effects of cytokines on hypothalamic releasing factors
have been included in Table 5.
b. Effect of cytokines on CNS neurotransmitters
and central
neuronal activity. We have shown that administration of immune cell-conditioned media containing lymphokines and
monokines results in decreased NA content in the brain (279).
A summary of effects of natural purified or recombinant
cytokines on brain neurotransmitters and central neuronal
activity is given in Table 9 (52, 316, 324, 417-446). IL-1 reduces NA content and increases the ratio of 3-methoxy-4hydroxyphenylethylene glycol/NA, which reflects increased NA metabolism. This effect is observed in the
hypothalamus, hippocampus, brain stem, and spinal cord.
The fact that catecholaminergic fibers in the spinal cord are
stimulated by IL-1 may indicate one neural pathway for the
effect of this cytokine in the CNS. The stimulation of NA
neurons in the CNS by IL-1 is consistent with other evidence
showing that stimulation of CRH production by catecholaminergic neurons is involved in the response of the
HPA axis to IL-1. This is further supported by studies showing that the response of the HPA axis to IL-1 is blocked by
surgical interruption of noradrenergic innervation of CRHproducing neurons in the paraventricular nucleus of the
hypothalamus or by NA antagonists (307,309,447,448). IL-1
and IL-6 stimulate dopamine metabolism in the striatum,
hippocampus, and prefrontal cortex. These cytokines also
stimulate serotonin metabolism and release, but the effect is
observed predominantly in the hippocampus. However, IL-1
causes a general accumulation of tryptophan in the CNS.
IL-2 inhibits potassium-induced release of acetylcholine
from slices of the hippocampus. IL-3, IFNy, G-CSF, and GMCSF augment choline-acetylcholine transferase activity in
septal neurons in vitro.
Studies performed in vivo show that IL-1 administration
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
79
TABLE 8. Effects of cytokines on the thyroid gland
a. In Vivo
Cytokine
Species
Administration
IL-1/3
Rat
sc
IL-1/3
Rat
Minipump
IL-1/3
Rat
IL-1
IL-la
Mouse
Mouse
Continuous infusion
into CSF
Continuous sc infusion
Continuous 7 days
TNFa
Rat
iv, 1 or several
TNFa
Rat
Continuous infusion,
ip minipump
TNFa
TNFa
Mouse
Human
ip 3 days
iv
Effect
Ref.
4 Total serum T4 and T3; | free T4 due to 4 secretion, not to j catabolism
4 Free T4 (first 2-4 days), 1 plasma total T4 and T4
binding the whole week. Depending on dose, 4
plasma TSH, impaired TSH responsiveness to TRH
4 Plasma T4, TSH only 4 after 7 days By 24 h, 4
proTRH mRNA in PVN
4 Serum T4 and T3
4 Serum T4 due to inhibition of release, thyroid in
vitro unresponsive to TSH, f pituitary TSH 22
and 31 days after treatment
4 Serum TSH, T4, free T4, T3 and hypothalamic TRH
pituitary TSH/3 mRNA, thyroid 125I uptake and T 4
and T3 release in response to TSH, no change in
TSH response to TRH
4 T4, 4 binding of T4 in plasma caused by reduction
of T4-binding prealbumin, no effect on basal or
TRH-stimulated TSH levels.
4 rT3, | T3/T4 ratio, 4 T3 and T4 responses to TSH
4 T 3 and TSH, | rT3, T4 and free T4 not affected
372
323
373
374
375
334
376
377
378
b. In Vitro
Cytokine
Species
Effect
Ref.
IL-1/3
IL-1/3
IL-la,/3
IL-la,/3
IL-la,/3
Rat thyroid cell culture
Human, normal, and thyrocytes Graves'
Human, thyrocytes Graves'
Human thyroid cell culture
Human thyrocytes
4
f
4
4
4
Growth
or 4 TSH-induced TRG release (dose-dependent)
TSH-induced TRG release
TRG secretion and cAMP
125
I incorporation and iodothyronine release
379
380
381
379
382
IL-6
IL-6
Human thyrocytes
Human thyrocytes Graves'
No effect
4 TSH-induced T 3 secretion and thyroid peroxidase
mRNA
383
384
TNFa
TNFa
Human thyrocytes
Human
4 125I incorporation and iodothyronine release
Blunted TSH-induced TRG release
382
IFNy
Human, thyrocytes normal and Graves'
386
IFNy
Human thyrocytes
4 TSH-stimulated human TSH receptor gene expression
4 125I incorporation and iodothyronine release
385
382
CSF, cerebrospinal fluid; sc, subcutaneous; TRG, thyroglobulin.
stimulates neurons of the paraventricular and supraoptic
nucleus of the hypothalamus as well as neurons of the stria
terminalis. IL-2 and IFN7 stimulate neuronal activity in the
cortex and hippocampus. In contrast, IL-1 and IL-6 exert an
inhibitory action on neurons of the anterior hypothalamus.
In brain slices, IL-1 stimulates neurons of the supraoptic
nucleus of the hypothalamus, an effect that is modulated by
y-aminobutyric acid (GABA)-ergic inputs. This cytokine inhibits long-term potentiation in the hippocampus and decreases voltage-gated calcium currents in dissociated CA1
neurons. TNF and IFN7 also inhibit long term potentiation.
IFN7 exerts an excitatory effect in CA3 pyramidal cells and
decreases evoked inhibitory potential amplitude. TNF stimulates neurons of the organum vasculosum of the lamina
terminalis.
c. Effect of immune-derived
products on peripheral nerve
activity. Another way through which neuro-endocrine structures could receive information from the immune system is
the action of immune-derived products on peripheral nerve
fibers. Although the effects of cytokines on peripheral nerves
have not been explored as widely as those on the CNS, some
data are available.
SP increases markedly in cultures of superior cervical ganglia grown in the presence of conditioned medium from
concanavalin A-stimulated splenocytes. The effect is mimicked by IL-1, does not involve nerve growth factor, and
seems to be somewhat specific since the activities of tyrosine
hydroxylase and tryptophan hydroxylase are not altered
(449,450). IL-1 does not act directly upon neurons to raise SP,
but rather through the induction of leukemia inhibitory factor (451). It has also been shown in vitro that IL-1 suppresses
the evoked NA release from rat myenteric nerves (452).
The in vivo evidence that administration of cytokines affects peripheral nerve activity does not indicate whether the
effect is primarily exerted at peripheral or central levels. For
example, systemic administration of IL-1 increases the rate of
firing of splenic nerve fibers (453). Intraperitoneal injection
of IL-1/3 into rats also produces an increase in NA levels in
the spleen, as determined by in vivo microdialysis (454), and
accelerates NA turnover in the spleen, lung, diaphragm, and
BESEDOVSKY AND DEL REY
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Vol. 17, No. 1
TABLE 9. Effect of cytokines on CNS neurotransmitters and central neuronal activity
a. In Vivo
Cytokine
Effect
Ref.
I NE in Hy and BS; f MHPG/NE forebrain, BS, and spinal cord; t Trp in all
brain regions and in the cervical spinal cord
4 NE and E; | MHPG in Hy, | HVA in Str and Hy medulla; MHPG and NE
changes in Hy blocked by indomethacin
Push-pull to infuse and collect, medial basal Hy, f DA and DOPAC
Microdialysis to inject and collect into AHy, t release of NE, DA, 5-HT, MHPG,
DOPAC, HVA, and 5-HIAA
Microdialysis in Hip, intraHip administration, f 5-HT
icv; T extracellular 5-HIAA in anterior Hy
1 Cerebral concentration MHPG (largest in Hy, medial division); f Trp throughout the brain
ip; t MHPG, 5-HIAA and Trp, but not DOPAC
f NE turnover in Hy and Hip, f 5-HT turnover in Hip and prefrontal Cx; f DA
utilization in prefrontal Cx
icv, c-fos mRNA in Hy and immunoreactivity in PE, PVN, SON, ARC, SuM
Lateral ventricle, blocks spontaneous expression of c-fos protein in the nucleus of
LH-RH neurons between 1730 and 1800 h on proestrus.
iv; I immediate-early gene c-fos expression in CRF and oxytocin-producing cells of
the PVH. Also cell groups in bed nucleus of the stria terminalis, the central nucleus
of the amygdala, the lateral parabrachial nucleus, and the dorsomedial and ventrolateral medulla
iv; f electrical activity of single neurons in the PVN
No alterations in MUA discharge of POA/AH but 4 EEG synchronization
iv; i MUA in lateral margin of AHy
iontophoretically or by micropressure into bed nucleus of stria terminalis, single
unit extracellular recording; marked excitations of long duration
I NE turnover in Hy and DA turnover in prefrontal Cx, but not 5-HT
icv; I neuronal Cx and Hip activity
t 5-HT and DA activity in Hip and prefrontal Cx, but does not affect central NE
activity
Microiontophoretic application, t single cell neuron activity in Cx and Hip
417
Species
IL-1/3
Rat
IL-1
Rat
IL-1/3
IL-1/3
Rat
Rat
IL-1/3
IL-1/3
IL-la,/3
Rat
Rat
Mouse
IL-la,/3
IL-1/3
Mouse
Mouse
IL-la
IL-1/3
Rat
Rat
IL-1
Rat
IL-1/3
IL-1/3
IL-1/3
IL-1/3
Rat
Rat
Mouse
Rat
IL-2
IL-2
IL-6
Mouse
Rat
Mouse
IFNy
Rat
418
419
421
316
420
422
423
424
425
324
426
427
428
26
429
424
431
424
432
b. In Vitro
Cytokine
Species
Effect
Ref.
In Cx synaptic preparations, | GABAA receptor function
Hy, f release of NE and DA
Hy slices, | release of monoamines
Brain slices; f firing of in 60% neurosecretory neurons in the SON (intracellular
recordings)
f And prolonged synaptic inhibition (intracellular recording of hippocampal pyramidal cells of the CA1 region)
Depolarizes membrane potentials in most SON neurons
Local GABAergic inputs modulate IL-induced excitatory responses (intracellular recordings in slices)
4 voltage-gated Ca 2+ current in acutely dissociated hippocampal CA1 neurons
(whole-cell patch clamp)
Hip slices, | LTP of the slope of the population excitatory postsynaptic potential
and the population spike amplitude in CA1
Hip slices, 4 K-evoked, but not the basal, release of ACh
Embryonic primary septal neurons, | ChAT activity
Isolated median eminence, | stimulation-evoked release of NE from noradrenergic
axon terminals. No effect on spleen NA release.
Hip slices; extracellular recording, Cal region from stratum pyramidale and stratum
radiatum, f basal neurotransmission, f LTP after long lasting application
Slices; extracellular single-unit recordings, | firing rate 44% neurons in OVLT
433
434
421
435
IL-1/3
IL-1/3
IL-1/3
IL-1/3
Mouse
Rat
Rat
Rat
IL-1/3
Rat
IL-1/3
Rat
IL-/3
Guinea pig
IL-1/3
Rat
IL-2
IL-3
TNFa
Rat
Mouse
Rat
TNFa
Rat
TNFa
Guinea pig
IFNy
IFNy
IFNy
Rat
Rat
Rat
Embryonic septal nuclei with adjacent basal forebrain, f ChAT activity and mRNA
Hip slices, I STP, 4 LTP
Hip slices; excitatory effect on CA3 pyramidal cells and 4 evoked inhibitory
postsynaptic potential amplitude
444
445
446
G-CSF
GM-CSF
Mouse
Mouse
Embryonic primary septal neurons, | ChAT activity
Embryonic primary septal neurons, f ChAT activity
440
440
436
437
438
439
52
440
441
442
443
ACh, Acetylcholine; ChAT, choline acetyltransferase; Trp, tryptophan; HVA, homovanillic acid; NE, norepinephrine; DA, dopamine; 5-HT,
5-hydroxytryptamine; MHPG, 3-methoxy 4-hydroxy-phenylglycol; DOPAC, 3,4-dihydroxyphenylacetic acid; 5-HIAA, 5-hydroxyindole-3-acetic
acid; GABAA, gamma-aminobutyric acidA; Hy, hypothalamus; Hip, hippocampus; Str, striatum; BS, brain stem; POA, preoptic area; AHy,
anterior hypothalamus; MUA, multiunit activity; EEG, electroencephalogram; Cx, cortex; OVLT, organum vasculosum lamina terminalis; LTP,
long term potentiation; STP, short term potentiation; PE, periventricular; PVN, paraventricular nucleus; SON, supraoptic nucleus; ARC,
arcuate nucleus; SuM, supramammillary nucleus; f , stimulate or increase; 4 , decrease or inhibit.
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
81
pancreas without appreciable effects in other organs (455).
profound effects on behavior, e.g. learning and explorative
IL-6 does not affect NA turnover. Thus, while both cytokines and avoidance behavior (476,477). Some of these actions are
are effective for adrenocortical activation, only IL-1 increases likely to occur at CNS levels since intracerebroventricular
administration of IL-lra blocks such effects (478). Cytokines
sympathetic nerve activity (454, 455). However, since IL-1
may be involved in the central mechanisms for learning and
administered intracerebroventricularly also induces an inmemory since IL-1, TNFa, and IFNy inhibit long-term pocrease in splenic NA turnover, the stimulation of the symtentiation, a mechanism that is thought to underlie these
pathetic activity seems to be, at least in part, centrally meprocesses (464).
diated (454-456).
/. Effect of cytokines acting in the brain on peripheral immune
Antigens trapped in the spleen and immune cells that
functions. Cytokines acting on the CNS can affect immune cell
home in this organ are derived from the circulation. Therefunctions. For example, intracerebroventricular infusion of
fore, the blood flow of this organ plays an important role in
IL-1 decreases cell-mediated immune responses, natural
splenic immune functions. We have recently observed that
killer cell activity, the response to mitogen, and IL-1 and IL-2
IL-1 causes an increase in splenic blood flow. This effect is
production (308,479). Blockade of HP A axis stimulation and
abrogated by surgical interruption of splenic nerve fibers
of sympathetic nervous system activation by IL-1 not only
(457).
reverses these effects but also causes an increase in the proThere are indications that afferent neural pathways may
duction of IL-1 by splenic macrophages (308, 479).
mediate effects of cytokines on the brain. Vagotomy interferes with behavioral alterations that follow LPS adminis3. Metabolic effects of cytokines. It is quite obvious that because
tration (458). The increases in brain tryptophan caused by
of the variety of mechanisms involved, the activation of the
intraperitoneal injection of endotoxin or IL-1 are prevented
immune-neuro-endocrine network will have an impact on
by pretreatment with the ganglionic blocker chlorisondamgeneral host homeostasis. Metabolic derangements occur
ine. Thus, the autonomic nervous system appears to be inwhen the immune system is activated during inflammatory,
volved in the IL-1-induced changes in brain tryptophan
infective, and neoplastic processes (480-485). There is evi(459).
d. Effect of cytokines on neuronal growth and differentiationdence
and that such derangements are mediated, at least in part,
by immune-derived cytokines such as IL-1 and TNF (486nerve repair. Cytokine-containing supernatants obtained
491). The effect of these cytokines is exerted either directly or
from activated lymphocytes maintain sympathetic neurons
in culture (460). IL-1, IL-6, IFNy, and TNFa stimulate pro- through their action on neuro-endocrine mechanisms. In this
section, the effect of IL-1 on glucose metabolism is given as
liferation of astroglial cells and neurons (461). The effects of
an example of the capacity of an immune-derived product to
IL-3 seem to be more specifically directed to neurons since
affect a parameter which, under physiological conditions, is
this cytokine preferentially stimulates neurite outgrowth of
cholinergic neurons (462). IL-1 stimulates the activity of cho- under multifactorial regulation.
Alterations in glucose blood levels are detected during the
line acetyltranferase in cultures of sympathetic ganglia (463).
course of certain pathological conditions in which IL-1 is
IL-1 can also influence nerve cell growth since it induces the
production of nerve growth factor in vitro (464). Additional known to be produced. Administration of nanogram
details on the involvement of immune cytokines in the conamounts of IL-1/3 into mice of different strains results in
trol of neuronal cell growth and differentiation and nerve
decreased glucose blood levels. Insulin levels are increased
repair under pathological and probably also during physi2- to 3-fold for about 4 h when IL-1 is injected into endotoxinological conditions can be found in specific reviews (465resistant C3H/HeJ mice. However, no changes in the levels
467).
of this hormone were observed in parallel to the hypoglye. Effect of cytokines on thermoregidation, food intake, sleep,cemia
and induced by IL-1 in three other strains of mice that are
behavior. Immune cytokines influence complex mechanisms not endotoxin resistant. Functional tests for glucose tolerance
that involve a variety of neuronal circuits such as thermowere performed in mice who had previously received single
regulation, food intake, sleeping patterns, and behavior. As
or repeated injections of IL-1 (487). This treatment results in
stated in the introduction, these effects will not be discussed
an accelerated glucose clearance. Furthermore, in spite of the
in detail since recent reviews have been published. We shall
administration of exogenous glucose, these animals develop
mention here only a few examples. The notion of the exisa long lasting hypoglycemia. It appears therefore that the "set
tence of an endogenous pyrogen is now fully established
point" of the regulatory mechanisms that stabilize glucose
with the exception that not one, but several, endogenous
concentration in blood is adjusted to a lower level after IL-1
substances, such as IL-1, IL-6, IL-8, IFN7, IFN/3, and GM-CSF treatment (487).
(468-470), possess the capacity of inducing fever. Also, sevIncreased adrenaline and glucocorticoid output from the
eral cytokines inhibit food intake, among them IL-1, IL-6, adrenals is a major counterregulatory mechanism tending to
IL-8, and TNFa (469, 471). The capacity of increasing slow
normalize glucose blood levels during hypoglycemic states.
wave sleep is also shared by different cytokines such as IL-1,
Adrenalectomy abrogates these mechanisms and results in
IL-2, IFN7, and TNFa (472, 473). A dual role of cytokines in
reduced glucose production. When IL-1 is administered to
the sensitivity to pain has been described. IL-1 and IL-6,
adrenalectomized animals, the hypoglycemia thus induced
acting at sites of inflammation, sensitize afferent fibers by
is more pronounced than in normal mice and is paralleled by
stimulating the release of prostaglandins (474). However,
a marked reduction in insulin blood levels. Thus, there is a
when IL-1 is given systemically, it mediates an antinocicepdissociation between insulin and glucose levels in adrenative response (475). Several cytokines are known to exert
lectomized mice that received IL-1. These data, taken to-
82
BESEDOVSKY AND DEL REY
gether with the results mentioned above, suggest that IL-1induced hypoglycemia cannot be explained by an insulin
secretagogue action of this cytokine. Therefore, it is possible
that IL-1 is involved in the increased non-insulin-mediated
glucose uptake observed during sepsis (492).
This led us to study the effect of IL-1 in two mouse strains
that are models of insulin-resistant diabetes. Genetically diabetic C57B1/Ks db/db and C57B1/6J Ibm ob/ob mice are
both hyperglycemic and markedly hyperinsulinemic; furthermore, they have fewer insulin receptors and are resistant
to the exogenous administration of insulin. We found that
IL-1 also acts as a hypoglycemic agent in this type of diabetic
animal (493). Interestingly, it has been recently reported that
TNF expression is increased in these animals and that this
cytokine induces insulin resistance (494, 495).
In normal rats, the hypoglycemic effect of IL-1/3 is modest.
A likely mechanism that could explain this is the reduction
in insulin levels observed in rats after IL-1 administration
(487, 496) that occurs in parallel to the release of glucocorticoids and catecholamines. Although other authors, using
another source of the cytokine, have reported that IL-1/3
induces hyperinsulinemia in normal rats (497), all reports
agree that this cytokine induces a marked hypoglycemia and
a profound decrease in insulin levels in adrenalectomized
rats (487, 498).
It has been reported that, in contrast to mice (487), repetitive injections of IL-1 to rats cause a degree of glucose intolerance (499). This can also be explained by both the reduction in insulin release and the effect of counterregulatory
hormones. It is, however, noteworthy that IL-1 exerts more
profound effects in insulin-resistant Zucker fa/fa rats than in
control rats since it normalizes several metabolic parameters,
including glucose tolerance (500).
Several mechanisms seem to contribute to IL-1-induced
hypoglycemia (501). It was reported that IL-1 inhibits glucocorticoid-induced hepatic gluconeogenic enzymes (502)
and stimulates glucose transport in adipocytes and fibroblasts (503, 504). These results agree with a previous report
showing that a macrophage-derived factor causes increased
glucose transport and oxidation (505).
Central mechanisms also seem to participate in mediating
the hypoglycemic effect of IL-1. Intracerebroventricular injection of the cytokine induces hypoglycemia (506), and glucose-sensitive neurons in the ventromedial hypothalamus
are affected by this cytokine (507).
As previously mentioned, the effect of IL-1 on glucose
metabolism is only one example of how an immunologically
derived product can affect essential processes related to general homeostasis. Other lymphomonokines, such as TNF, can
also affect general metabolism (490).
III. Immune-Neuro-Endocrine Circuits
Most of the information discussed so far derives from
studies based on pharmacological or surgical manipulations
of neuro-endocrine mechanisms and on administration of
immune-derived products. These studies suggest that there
may be a tonic control of the immune system by hormones,
neurotransmitters, and neuropeptides, on the one hand, and
Vol. 17, No. 1
that immune-derived products, such as cytokines, can affect
neuro-endocrine mechanisms, on the other. However, the
regulation of any physiological system is based on dynamic
interactions between the physiological variable and regulatory systems. Thus, we have proposed and provided experimental evidence showing that neuro-endocrine responses
mediated by immune-derived products are elicited after activation of the immune system (281, 279). Such responses
indicate the operation of a network of interactions between
immune-derived signals and hormones, neurotransmitters,
and neuropeptides. Moreover, the operation of this network
is of importance for immunoregulation, host defenses, and
homeostasis. The examples that we shall discuss in the following are classified either as long loop or as local interactions. Long loop interactions refer to processes in which the
stimulation of the immune system results in the release of
immune-derived mediators that can, in turn, affect distant
neuro-endocrine structures. In contrast, local interactions are
those in which both immunologically derived and neuroendocrine agents exert reciprocal effects within the tissue or
organ where they are released. This classification is to some
extent arbitrary, since, for example, it is possible that interactions occurring initially at a local level, either within a
peripheral tissue or within the brain, could subsequently
affect distant neuro-endocrine mechanisms. A schematic representation of immune-neuro-endocrine networks is shown
in Fig. 2.
A. Long loop immune-neuro-endocrine circuits
As mentioned, there is abundant evidence that neuroendocrine and metabolic alterations parallel infective, inflammatory, autoimmune, and neoplastic diseases. These
alterations could be directly caused by the infective agent or
neoplastic cells and/or their products, or by the tissue injury
that they may induce, and be, therefore, the consequence of
the disease. Alternatively, the changes in neuro-endocrine
functions and intermediate metabolism observed during certain pathologies may be mediated by factors released when
the immune system is activated. These changes may constitute part of host-mediated mechanisms that could, in turn,
affect the operation of the immune system. The identification
of which immune-derived factors are affecting neuro-endocrine and metabolic processes during a given disease, and
whether they are ameliorating or aggravating its course, is of
clinical relevance. Thus, immunologically mediated neuroendocrine responses may be beneficial for the host, but, under certain circumstances, they might become detrimental
(see discussion below).
Several strategies have been used to distinguish between
neuro-endocrine effects related to the activation of the immune system itself and those that are consequences of the
disease. Although other strategies may still be proposed, the
following is a list of those for which examples are available:
1. To trigger immune responses with innocuous, noninfective, nonneoplastic antigens and to search for changes in
endocrine, central, and peripheral neural activity occurring
subsequent to the activation of the immune system.
2. To show that direct contact of immunological cells with
disease-causing agents, in which neuro-endocrine alterations
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
Psycho-sensorial Stimuli
Behaviour
CNS
Immune and
Neuroendocrine
Products
Endocrine
System
(Hormones)
and
Immune
Cell
Products
Peripheral
Nervous
System
(Neurotransm.
Neuropeptides)
Immune and
Neuroendocrine
Products
IMMUNE SYSTEM
Antigenic Stimuli
Immune Response
FIG. 2 The CNS and the immune system exchange information
using hormones, neurotransmitters, neuropeptides, and immune
cell-derived products as mediators. The box representing the immune system includes not only the classic immunological organs,
but also all peripheral tissues where an immune response may take
place. The endocrine and the peripheral nervous systems are represented together because of their multiple interconnections. When
the exchange of signals occurs between immune and neuro-endocrine structures that are distant from each other, a long-loop circuit
is established. When immune-neuro-endocrine communication is
based on exchange of paracrine signals, either at peripheral or at
central levels, local interactions are established (circles within
boxes). Long-loop circuits and local interactions are also interconnected. The degree of activity of the immune-neuro-endocrine network can be affected at the level of the immune system, after
internal or external antigenic challenge, or at the level of the CNS,
by sensorial and psychosocial stimuli. The branching out arrows
symbolize the consequences of interactions between immune, endocrine and nervous systems for the whole organism.
83
are observed, induces the production of mediators capable
of eliciting similar neuro-endocrine changes in healthy
individuals.
3. To confirm that neuro-endocrine alterations occurring
during diseases that involve the immune system are not
expressed in individuals lacking the particular type of immunological cells involved.
4. To establish that neuro-endocrine changes that follow
administration of infective and neoplastic agents that stimulate the immune system are detectable before the overt
onset of the disease.
In the following, we provide information about long loop
immune-neuro-endocrine interactions with particular reference to our own work. In this context, probably the most
extensively studied circuit is the one based on the capacity
of the immune system to affect the activity of the pituitaryadrenal axis. Increased glucocorticoid blood levels have been
observed during the course of specific immune responses to
different innocuous antigens (202, 280, 508, 509). These
changes are only detected when the immune responses are
intense enough to reach a given threshold. For example,
when the Biozzi high-low responder strain of mice is used,
significant increases in corticosterone blood levels are observed only in immunologically high responder animals
(510). It has been argued that the magnitude of the effect of
specific immunization on the pituitary-adrenal axis is modest when compared with that observed after acute administration of individual cytokines (511). In our view, these
effects cannot be compared, since immunization causes, in a
threshold-dependent manner, a 3- to 4-fold increase in glucocorticoid blood levels that is sustained over several days.
In contrast, a bolus injection of certain cytokines, such as IL-1,
results in stimulation of the HPA axis to a more marked
degree, also depending on the dose administered, but lasting
for a few hours only.
Profound increases in ACTH and corticosterone blood
levels are also observed after mice are inoculated with Newcastle disease virus (NDV), a virus that produces a mild
disease in rodents (282, 289, 512). Two hours after injection
of this virus, the levels of ACTH and corticosterone in blood
are already increased several fold. This effect is not caused
by the virus itself or by the stress of the infection but by the
release of lymphokines or monokines from immunological
cells. It was shown that IL-1 is the main cytokine involved in
stimulation of the HPA axis after administration of the virus.
These studies provided the first evidence that IL-1 can mediate the increase in glucocorticoid levels after the administration of a natural infective agent (282).
It has been known for a long time that bacterial endotoxins
can stimulate the pituitary-adrenal axis. This increase in glucocorticoid levels has protective effects during septic shock
(513). More recently it has been shown that endotoxin stimulation of the pituitary-adrenal axis is caused by products
from activated macrophages (514) and that IL-1 is the main
mediator of this effect (290).
An early increase in glucocorticoid blood levels is also
observed after syngeneic tumor transplantation (515). In at
least one model, this effect is mediated by factors derived
from immunological cells (516-518). A biphasic increase in
glucocorticoid levels is observed after administration of EL-4
84
BESEDOVSKY AND DEL REY
lymphoma cells. The early 8- to 10-fold increase in corticosterone blood levels occurs within 24 h after tumor cell transplantation, well before the tumor becomes detectable. The
presence of T cells is required to elicit such changes in glucocorticoid levels. Furthermore, a host-derived factor present
in the ascitic fluid of animals bearing an EL-4 lymphoma
stimulates the pituitary-adrenal axis upon transference to a
normal host (516, 518).
Not all types of immune responses result in stimulation of
the pituitary-adrenal axis. During skin graft rejection, corticosterone blood levels are lower than in animals bearing
autografts (519). A more recent report showed that major
alterations in the processing of POMC in the pituitary gland
are observed during skin graft rejection (520).
Several other endocrine processes are affected during the
course of activation of the immune system. Reduced levels
of circulating thyroid hormones during the immune response to innocuous antigens such as sheep red blood cells
(SRBC) and trinitrophenylated-hemocyanin have been reported (280). This finding may explain the inhibition of thyroid function that is observed during infective diseases (521).
Early increases in PRL blood levels occur after administration of Freund's complete adjuvant to rats (522). Inoculation
of 1 X 106 cells from methylcholantrene- or dimethylbenzantracene-induced tumors, but not of normal cells, causes a
clear increase in PRL and corticosterone and a decrease in T4,
insulin, and testosterone blood levels after 24-48 h (515).
These endocrine changes precede the overt appearance of the
tumor by several days, and there is a lack of correlation
between the progression of the tumor and the majority of the
endocrine alterations observed. This fact suggests that these
hormonal changes are not directly mediated by tumor cell
products but rather constitute a host response to endogenously induced mediators capable of affecting neuro-endocrine mechanisms.
The autonomic nervous system is also affected during
activation of the immune system. The NA content in lymphoid organs of animals bred under conventional conditions
is lower than in those of immunologically less active, germfree animals (523). We have also observed decreased sympathetic activity in the spleen during the immune response,
as evaluated by the NA content and turnover rates (195,524,
525). Administration of Freund's complete adjuvant induces
a decrease in the total content of NA in the spleen that lasts
several days (526). These findings indicate that sympathetic
activity is reduced during certain immune responses. However, other authors have shown that, after inoculation of
Freund's complete adjuvant into rats, the sympathetic and
cholinergic nerve activity in submaxillary lymph nodes is
increased (527). As it will be discussed in Section B below,
interactions between the autonomic nervous system and immune mechanisms are difficult to classify as long loop or as
local immune-neuro-endocrine interactions.
From the data concerning endocrine and autonomic responses during activation of the immune system, it cannot be
concluded that the CNS is directly involved in all of the peripheral effects discussed above. However, the observed
changes in the endocrine and autonomic nervous systems reflect, if only indirectly, the existence of afferent pathways in
immune-brain communication. Since the hypothalamus inte-
Vol. 17, No. 1
grates most endocrine and autonomic functions, the possibility
that hypothalamic neurons receive signals derived from the
immune system was explored. It was shown that after inoculation of SRBC or trinitrophenylated-hemocyanin, the frequency of firing of neurons in the ventromedial nucleus of the
hypothalamus is increased several fold at a time close to the
peak of the immune response (528). No statistically significant
changes were detected at the time of the peak immune response
to SRBC in the arcuate, premamillaris dorsalis, and paraventricular nuclei and in the pre-optic, anterior, and posterior areas
of the hypothalamus, and in the reuniens thalamic nucleus
(200). The results of these experiments, which were performed
in anesthetized rats, show that the hypothalamic response does
not involve general neuronal activation after antigenic challenge. In fact, they suggest that the information derived from
activated immune cells follows specific pathways. Neuronal
multiunit activity was also studied in the hypothalamus of
freely moving, conscious rats using chronically attached recording electrodes. Changes in the rate of firing of neurons of
the paraventricular hypothalamic nucleus and in the anterior
hypothalamic area were detected after immunization with
SRBC (529).
The hypothalamus is subject to hormonal feedback signals. Therefore, it cannot be decided whether a change in
the electrical activity of hypothalamic neurons is causally
related to the reception of immune messages or to the
emission of endocrine signals. Furthermore, some hypothalamic neurons are influenced by neurotransmitters that
are derived from neurons that follow anatomically well
identified pathways, connecting the hypothalamus with
distant parts of the brain. Aminergic neurons projecting to
the hypothalamus are important regulators of hypothalamic neuronal activity. On this basis, catecholamine
turnover rates in different regions of the CNS during the
immune response to SRBC were studied (279). In immunologically, high-responder rats, a marked decrease in
hypothalamic NA turnover rate compared with salineinjected controls was noted 4 days after antigen administration, whereas immunologically, low-responder animals had turnover rates almost equal to those of the
controls. This effect seems to be specific since no changes
in dopamine turnover in the CNS were observed during
the immune response. Other authors have shown that,
during the immune response to SRBC, the NA content is
markedly reduced in the paraventricular nucleus of the
hypothalamus (530). This effect of immune stimulation on
the CNS may explain the changes in NA content of the
hypothalamus that have been observed after inoculation of
Newcastle disease virus (512). In addition, the administration of muramyl dipeptide, which is cleaved from membrane walls of gram-negative bacteria and induces several
cytokines, was shown to cause a reduction of serotonin
metabolism in the CNS (531).
The endocrine and autonomic changes and the changes in
electrical activity and turnover rate of catecholamines in the
brain after activation of the immune system constitute clear
evidence of the reception of immune-derived signals by the
CNS.
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
B. Immune-neuro-endocrine circuits operating at local levels
All tissues, including those from the so-called immune
privileged organs, contain resident immune cells. During
certain pathological conditions, resident cells of the macrophage lineage become activated, and one of their main functions is to provide adequate antigenic presentation to lymphoid cells that are either already in the tissue or are derived
from the circulation. These events, which lead to specific
immune responses, occur in parallel to the recruitment, in a
particular sequence, of other types of leukocytes that are
involved in nonspecific immunity and inflammatory processes. These cells and their products coexist with hormones
reaching the interstitial space as well as other substances,
including biogenic amines and neuropeptides such as SOM,
SP, and VIP, which are locally produced by the diffuse neuroendocrine system (532,533). Peptide hormones generated by
immune cells might be also present. Mucosa and epithelium
are the interface with the external milieu. In these tissues,
products from immune and neuro-endocrine cells and antigens interact most intensively, particularly since they possess lymphoid aggregates that are in contact with the local
flora, such as the Peyer patches in the gut (534).
Specialized primary and secondary lymphoid organs,
apart from being the organs in which immune cells develop,
are also potential sites of immune-neuro-endocrine interactions. As mentioned before, these organs are extensively
innervated by autonomic and peptidergic fibers. Furthermore, local production of peptides such as vasopressin, oxytocin, and VIP, as well as steroid hormones, have been detected in the thymus (237, 238, 535).
As mentioned in previous sections, there is evidence that
cytokines can affect the activity of peripheral nerves and that
certain neurotransmitters and neuropeptides can influence
cytokine production. Even antibodies are potential mediators of peripheral immune-neural interactions since the Fc
part of immunoglobulins can bind to peripheral nerve fibers
in normal animals (536). Local immune-neuro-endocrine interactions can also be established in the CNS since, as mentioned above, several cytokines can be produced by both glial
and neuronal cells, implying the coexistence of these mediators with neurotransmitters and neuropeptides in the brain.
Furthermore, there is evidence that activated T cells can cross
the blood-brain barrier and migrate into the CNS (537, 538).
These cells may establish local immune-neuro-endocrine interactions in the CNS through the local release of cytokines
that can affect the activity of neural cells.
When this information is compiled, there is anatomical,
biochemical and pharmacological evidence suggesting that
functional immune-neuro-endocrine interactions can occur
at local levels. However, these functional interactions are
difficult to detect because they are assumed to occur in a
paracrine fashion and in restricted areas of specialized tissues. Furthermore, it is difficult to establish whether the
effect of an immune process is not the consequence of nonimmunological stimuli that parallel a given disease. For example, the production of sensory peptides in sites of inflammatory or local immune processes may not necessarily be
induced by interactions between immune cell products and
nerve fibers. Alternatively, they might reflect the conse-
85
quence of nociceptive and mechanical stimuli generated during inflammatory processes. These difficulties probably explain why there are not many examples of functional
immune-neuro-endocrine interactions locally within a given
tissue. However, some clues for such interactions can be
mentioned. Axonal reflex mechanisms contribute to the vascular and cellular components of localized inflammatory and
immune processes. Some cytokines may stimulate these
mechanisms since, through induction of prostaglandins, they
sensitize afferent nerve fibers (474). There is also evidence
that this reflex can be initiated by mast cell products (539).
Consequently, sensory peptides, like SP and neurokinin A,
are released; these can induce the production of the proinflammatory cytokine IL-1 and the expression of IL-2 receptors in gut-associated lymphoid tissues (266). Furthermore,
as mentioned above, some neuropeptides can affect mononuclear cell mobility. As a whole, these observations suggest
the existence of a local circuit involving immune cell products and neural mechanisms.
A further example can be derived from experiments showing that the altered function of enteric nerves in a model of
intestinal inflammation in nematode-infected rats is mediated by endogenous IL-1. The cytokine is most likely released
by macrophage-like cells in the myenteric plexus. In turn, this
cytokine-induced change in neurotransmitter content and
release is expected to affect immune cell functions, thus establishing a neuroimmune circuit in the myenteric plexus
(452, 540). A further example is the finding that, after instillation of food antigens in the rat intestine, a cholinergic
mechanism mediates an increase in the release of IgA and
IgG antibodies (541). However, the immunological mediation of this phenomenon needs further clarification.
As mentioned in the previous section, our studies and
those of others concerning changes in the activity of sympathetic nerves during activation of the immune system are
at present difficult to classify as local or long loop interactions. For example, the NA content in lymphoid organs of
animals bred under conventional conditions is lower than in
lymphoid organs of germ-free rats, in which immunological
stimulation by environmental antigens is markedly reduced
(523). This may indicate that immune-derived products affect sympathetic nerve activity in the lymphoid organs where
they are produced. These interactions would then be considered as occurring at a local level. However, and in contrast
to the other nonlymphoid organs studied, the NA content of
the adrenal gland is also decreased in the immunologically
more active rats. This indicates that an organ distant from the
main site of cytokine production is also affected, and, in this
case, immune-sympathetic interactions would be considered
as part of a long loop.
Local circuits could also be established during development, as illustrated by studies on the innervation of the
spleen in nude mice. These animals have a hyperinnervated
spleen as evaluated by histochemistry and by the NA content. When T lymphocytes, the cells these animals lack, are
injected or a thymus is implanted at birth, there is a reduction
in sympathetic fibers and in the content of the neurotransmitter in the organ (542). Therefore, T lymphocytes, which in
normal animals are in close contact with sympathetic fibers,
seem to provide a stop signal for the growth of the neural
86
BESEDOVSKY AND DEL REY
Vol. 17, No. 1
and IFNy, specifically protect T helper cells from the inhibitory effects of glucocorticoids (553-555). As the immune
response proceeds, the stimulation of the HPA axis will result in inhibition of the production of certain lymphokines
and/or monokines (250-254). In this way, the increase in
glucocorticoid levels induced by the immune response will
affect already activated cells with high affinity for the antigen
less than accessory cells or resting or low affinity lymphocytes. This is reflected by the phenomenon of sequential
antigenic competition. The levels of corticosteroids in blood
that are attained at the peak of the immune response to an
antigen inhibit the response to other unrelated antigens administered at this time. Such competition is, to a large extent,
abrogated by adrenalectomy or hypophysectomy (551,556).
On this basis, we have postulated that the regulatory function of the immune-HPA axis circuit is to prevent an inappropriate, excessive expansion and activity of immunological cells and overproduction of lymphokines and
C. Relevance of immune-neuro-endocrine circuits for
monokines.
immunoregulation
There are other examples of the potential discriminatory
In Section II.C, we gave examples showing that hormones, effects of neuro-endocrine signals that act predominantly on
neurotransmitters, and neuropeptides can affect defined
activated immune cells. After activation, lymphocytes exsteps and processes of the complex sequence of events that
press more receptors for certain hormones and neurotranslead to a specific immune response. However, neuro-endomitters. As previously mentioned, resting lymphocytes have
crine mechanisms that contribute to immunoregulation
no detectable receptors for insulin, whereas they are present
should not interfere with, and even preserve, immunospeciafter stimulation (3, 4, 557). Muscarinic and j3-adrenergic
ficity. Such a contribution could be based on a differential
receptors also increase after activation of lymphoid cells (22,
sensitivity of immune cells to neuro-endocrine agents, which
23). Thus, it is predominantly those cells activated by the
may depend on the state of activation of these cells after
antigen that will perceive hormonal or neurotransmitter
antigenic challenge. This implies that, to be efficient, a neuro- signals.
endocrine response should occur at a defined step of the
The particular location of immunological cells during the
immune process. This is clearly illustrated by the immuneimmune response could also determine the selective neural
HPA axis circuit.
effects on antigen-stimulated lymphocytes. The immune reGlucocorticoids have antiinflammatory effects, and they
sponse develops in well defined anatomical structures. After
can act as immunosuppressive agents. However, there is also
immunization of rats with SRBC, B cells producing specific
evidence that glucocorticoids can stimulate certain immune
antibodies appear first in the white pulp of the spleen close
mechanisms. These dual effects of glucocorticoids on the
to the periarteriolar sheath (558). This location, which is a T
immune system have been extensively reviewed (168, 169,
cell-dependent area, is optimal for T-B cell interactions. The
545). In the following, some of the effects of glucocorticoids
release of NA by sympathetic nerves in the spleen is prethat would indicate the relevance of the immune-HPA axis
dominantly restricted to the same zone (64, 65). Therefore,
circuit for immunoregulation are briefly discussed.
antigen-activated B cells would be more influenced than
It is well known that the immunosuppressive effect of
other B cells by sympathetic signals because of their location
glucocorticoids on immune responses is maximally exerted
in an splenic area with the highest NA content. Furthermore,
when the hormone is given before immunization (546, 547). they would be more affected by the phasic changes in splenic
This effect is less pronounced if the same dose is adminisNA content that are observed during the immune response
tered during the course of the immune response because
to SRBC (195). This decrease in NA content in lymphoid
resting B and T lymphocytes are more sensitive to glucocor- organs would result in increased blood flow, and, therefore,
ticoids than activated ones (548,549). Furthermore, antibody
influence immune cell traffic. Since resting and activated
synthesis by activated B cells can be stimulated by glucocor- lymphocytes display different homing and migratory patticoids (550, 551). Also, processes essential for the developterns, the neurally-mediated change in blood flow in imment of an immune response, such as antigen presentation
mune organs is expected to contribute to immunoregulation
and cytokine production, are glucocorticoid-sensitive (552).
(559).
The increase in glucocorticoid levels during an immune reAs described in parts A and B of this section, there are
sponse is a late phenomenon. It is, therefore, expected that
examples of activation of the immune system by innocuous
this endocrine change would not significatively interfere
antigens leading to the operation of immune-neuro-endowith antigen presentation, clonal expansion of activated lymcrine circuits. However, under natural conditions, the actiphocytes, and the initial production of immunoregulatory
vation of the immune system is often linked to pathological
cytokines. In this respect, it is noteworthy that IL-1, IL-2, IL-4, situations during which immune-neuro-endocrine circuits
and another factor present in supernatants of mitogen-stimcoexist with host mechanisms that are also affected as a
ulated spleen cells and distinguishable from IL-1, IL-2, IL-3, consequence of the disease. The following discussion will
fibers. This might explain why mice that develop strong
autoimmune processes and have a hyperactive immune system, such as MRL-lpr/lpr mice, show a progressive loss of
noradrenergic fibers in the spleen that correlates with the
progression of the disease (543). These findings, together
with the fact that splenic sympathetic innervation affects the
immune response, would indicate that bidirectional interactions between T cells and nerve fibers occur in the spleen.
It has been shown that experimental autoimmune encephalomyelitis is less severe when noradrenergic neurons in the
CNS have been destroyed (544). This finding suggests that
local immune processes in the brain can be influenced by
these neurons. This, together with the evidence that cytokines can affect the activity of noradrenergic neurons (417,
418, 421-423), may serve as an example of local immuneneural interactions at CNS levels.
February, 1996
k
1
•
*
4
•*
t
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
provide an example of the operation of these circuits during
pathological conditions.
The best characterized circuit is based on interactions between the immune system and the HPA axis. There is reasonable proof that normal bidirectional communication between these two systems can play a protective role whereas
disruption of this communication can lead to predisposition
to or aggravation of the disease. It is known that glucocorticoids in blood reach very high levels during sepsis. This
increase is protective for the host since administration of
sublethal doses of endotoxins such as LPS into adrenalectomized animals results in high mortality. It is now known that,
in this model of sepsis, the stimulatory effect of LPS on
glucocorticoid output is mediated by cytokines released by
macrophages (514), most likely IL-1 (290). Cytokines, which
stimulate the pituitary-adrenal axis, mediate the inhibition of
the inflammatory reaction that is observed soon after tumor
cell inoculation. One example is the previously described
effect of injection of EL-4 lymphoma cells (516). Twenty four
hours after injection of these cells, inhibition of the inflammatory reaction occurs in parallel to the immune cell-mediated increase in glucocorticoid blood levels. This antiinflammatory effect is not observed in adrenalectomized animals.
Another example of this modulatory action of the pituitaryadrenal axis is observed in Lew/N female rats, which are
susceptible to experimentally induced arthritis. These rats
have a defective HPA axis that is poorly stimulated by cytokines such as IL-1 (560). A clinical correlate is the disturbed
HPA axis of patients with rheumatoid arthritis (561).
As mentioned above, the immune-HPA axis circuit may
contribute to impede an excessive cumulative expansion of
immune cell mass and activity. Disturbances in this circuit
may contribute to the expression of lymphoproliferative and
autoimmune diseases in genetically predisposed individuals, especially since these pathological events are the product
of multiple factors that progressively disrupt immune cell
homeostasis. In support of this view is the finding that Obese
Strain (OS) chickens with spontaneous autoimmune thyroiditis do not respond to immunization with sheep erythrocytes
with any detectable elevation in circulating corticosterone,
which is in contrast to normal chickens (508, 545). OS chickens are capable of producing a factor that increases glucocorticoid blood levels upon injection into normal animals. The
main cytokine responsible for this effect has been identified
as IL-1 (562). However, OS chickens show a significantly
reduced glucocorticoid response to the injection of this factor. A disturbed immune-HPA axis communication has also
been found in murine models of lupus. After injection of IL-1,
lupus-prone mice may reach nearly the same levels of plasma
corticosterone as normal mice. However, since animals that
will develop the autoimmune disease have higher baseline
levels of plasma corticosterone, the increase in the concentration of this hormone was significantly lower than that of
normal mice (563). Another example of the relevance of the
immune-HPA axis circuit in the prevention or moderation of
autoimmune diseases derives from studies on experimental
allergic encephalomyelitis (EAE). Before and during the
overt clinical expression of the disease, increased glucocorticoid levels are observed. Such increased levels help to mod-
87
erate the clinical course of the disease since most adrenalectomized rats with EAE die during the first attack (564, 565).
In summary, there are examples showing that immuneneuro-endocrine circuits participate in immunoregulation. This evidence does not contradict the fact that the
immune system is also under control of very efficient
autoregulatory mechanisms. In our view, mechanisms under CNS control would come into operation, depending on
the intensity of the immune response and on the type of
mediators released. If this is the case, the regulatory outcome will be the result of external neuro-endocrine signals
and autoregulatory immunological mechanisms. Hormones, neurotransmitters, and neuropeptides could act
directly on defined subsets of immunological cells, or they
could synergize or antagonize the effect of immune system
autoregulatory mechanisms.
IV. Homeostatic and Antihomeostatic Functions of
the Immune System: Contribution to Natural
Selection
The preservation of a constant internal environment and
the establishment of optimal interactions between different
body constituents and the external world are the key features
of homeostasis.
The immune system contributes to homeostasis by recognizing and eliminating foreign and altered self-antigens, thus maintaining the appropriate cell types and molecules that constitute a tissue or organ at different stages
of life. However, homeostasis, as a product of natural
selection, contributes to evolution as long as the survival
of one individual would not threaten the survival of other
members of the species. In this sense, when referring to
homeostasis mediated by the immune system, it is necessary to consider that an individual infected by pathogenic
microorganisms may not only have his own life compromised but might also be a vector capable of transmitting
this agent to another healthy individual. Therefore, there
are conditions in which immune-mediated homeostasis
enters into conflict with evolution. This would be the case,
for example, when individuals who, although having a
fully operative immune system, cannot deal, or deal ineffectively, with an infective agent. The longer the individual who carries a pathogen survives, the higher is the
threat to the species. This conflict of interest between immune-mediated homeostasis and natural selection may be
overcome by mechanisms referred to as "anti-homeostatic" functions of the immune system. Evidence is accumulating that stimulation of the immune system is, under
certain conditions, detrimental and can lead to death of the
individual. This is clearly shown in experimental models
of sepsis. In such models, it would be easy to assume that
the main cause of death is the neuro-endocrine and metabolic derangements induced by the invading microorganism or by its products, e.g. bacterial endotoxins. However, in recent years, as specific cytokine antagonists and
blockers have become available, it has been shown that
certain cytokines such as IL-1 and TNF, rather than products from the infective agent that causes the disease, me-
88
BESEDOVSKY AND DEL REY
diate these deleterious neuro-endocrine and metabolic derangements during sepsis. For example, administration of
cytokine antagonists, specific antibodies, or soluble receptors protects animals from lethal effects of bacterial endotoxin (566-572). As mentioned before, LPS induces the
production of cytokines that, by stimulating the HPA axis,
cause a protective increase in glucocorticoid blood levels.
However, with high doses of endotoxin, this protection is
not sufficient and the levels of cytokines attained may
result in the death of the animal. One might ask why there
are not mechanisms efficient enough to impede the overexpression of genes whose products could cause self-destruction. A possible explanation is that these products
may mediate processes of "active" negative self-selection,
exerted by the immune system. These processes might
have been acquired in evolution to limit homeostasis when
the survival of the individual compromises the survival of
other members of the species.
Another way by which the immune system can contribute to evolution is through the association of immune and
reproductive functions. As mentioned in Section D, some
cytokines released during activation of the immune system interfere with the hypothalamus-gonadal axis (Table
5; Refs. 573-575). Although this is a speculative view, the
inhibitory effect of these cytokines on reproductive functions may serve to impede the transmission of microorganisms to the progeny via the placenta or the milk. Another situation in which the association of immune and
reproductive functions may lead to natural selection is
observed when the development of the immune system is
deficient. For example, nude mice (animals which genetically lack the thymus and therefore T lymphocytes) have
profound alterations in sexual functions. These mice, as
well as neonatal thymectomized mice, have a delay in
puberty and an altered sexual cycle. These defects can be
normalized by implantation of a thymus at birth. However, the alterations are still manifested when the animals
are immunologically reconstituted with T cells or raised
under germ-free conditions, thus allowing a normal life
span. In this case, it seems that the absence of the thymus
rather than immunodeficiency is the cause of the sexual
insufficiency (576). A similar situation occurs in chickens
in which the bursa of Fabricius is surgically removed
during embryonic life. These animals, in addition to lacking mature B lymphocytes, show a complete atrophy of the
oviduct at hatching, i.e. before they are exposed to environmental antigens. If a bursa is grafted during embryonic
life, this defect is not manifested (577). Therefore, a phenotypical association seems to exist between the function
of primary lymphoid organs that control the development
of the immune system and the reproductive capacity. Once
again, it appears that this association reflects a selective
force to impede the reproduction of immunodeficient animals, while favoring the reproduction of individuals capable of developing an efficient immune system.
In summary, there are indications that immune-neuroendocrine interactions may also contribute to natural selection. When the hyperproduction of endogenous immune
cytokines during transmissible diseases becomes deleterious, this results in a negative selective force. In this case, the
Vol. 17, No. 1
use of appropriate cytokine antagonists and blockers at certain stages of a disease may constitute an efficient way to
abolish deleterious immune-mediated neuro-endocrine and
metabolic derangements.
V. Outlook
A. The immune system as a diffuse, sensorial receptor organ
Information derived from stimuli from outside or inside
the organism is conveyed to the brain by specialized sensory
organs or receptors. Peripheral recognition and the initial
processing of this information are the first steps of any sen- *
sory event. Which of the signals received by the CNS will
become cognitive depends on adaptative programs integrated at CNS levels. In analogy to a sensorial organ, the first
step in any immune event is the recognition of the stimuli.
Immune cells are specialized, not only to detect foreign antigens, but also to distinguish normal from modified self- 1
antigens. Self antigens that are present on cell membranes
and body fluids could be considered as biological markers of
cell and tissue constancy and integrity. This implies that
immune cells, by using their large diversity of receptors, can
perceive an internal image of body constituents and react to
particular distortions of this image. It is now possible to add
that information processed by the immune system can also ^
be transmitted to the CNS or to brain-controlled structures.
Several messengers released by immunological cells, such
as lymphokines and monokines, certain complement fractions, immunoglobulins, histamine, serotonin, mediators of
inflammation, and thymic hormones, could serve as mediators of immune-CNS communication. Depending on the
type of antigenic stimulus, different possible combinations of
subsets of lymphoid and accessory cells and their soluble *
products can occur. Thus, it is conceivable that there exists
a code based on combinations of soluble messengers that
could inform the CNS about the type of immune response in
operation. Also, information about the site of an ongoing
immune response could be transmitted by stimulated nerve
fibers in the "strategically" located lymphoid organs or in
tissues where the immune response takes place. In our view,
the existence of an afferent pathway from the immune system to the CNS (281,279) implies that the immune system is
a receptor-sensorial organ.
*
The sensory function of the immune system does not imply that the CNS will always react to signals derived from
immune cells. As is the case with most information that the v
brain receives, immune messages would be subject to filtering mechanisms. A neuro-endocrine response to immune
signals occurs in a threshold-dependent manner, and only
seldom do such responses become cognitive. A cognitive
sensation is expected to be more often related to stimuli that
occur as a consequence of the disease rather than to the
immune response that the causal agent of the disease elicits.
Apart from the direct evidence already discussed that
activation of the immune system can affect brain functions,
another phenomenon might reflect the reception of signals "
from immune cells at CNS levels. It is well documented that
the magnitude of certain immune responses can be behaviorally conditioned (223-225). In our view, one of the mech-
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
anisms that underlies this phenomenon is based on the conditioning of neuro-endocrine responses related to changes in
the activity of the immune system. This neuro-endocrine
response that is integrated at CNS levels would ultimately
mediate the conditioned stimulation or inhibition of the immune response. This would constitute a further proof of the
sensorial capacity of the immune system since it implies that
this system is capable of informing the brain about the effect
of the unconditioned stimuli, e.g. an immunosuppressive
agent, on immune cells.
B. Is that all?
Endocrine feedback mechanisms and changes in certain
general variables such as glucose concentration in blood are
classic processes that serve to signal the brain about peripheral events. From the evidence discussed in the previous
sections, it is now possible to add that cells of the immune
system, through the production of certain cytokines and
other mediators, can also convey information to the CNS.
When cytokines function as mediators of an afferent pathway to the brain, they could be considered as part of a
retro-hormonal signaling system. The question that arises is
whether the evidence obtained from immune cells could
reflect a more general process by which other cells of the
body could also inform the brain about their functional state.
As well as immune cells, other types of cells receive signals
from outside the body, and, in all cases, are subject to intrinsic, genetically determined mechanisms that give rise to
products that control cell differentiation, turnover, and repair during different stages of life. Many of these products
either do not leave the cell or cannot reach the CNS. Furthermore, most cells are exposed to multiple autocrine and
paracrine signals and they establish dynamic contacts with
other cells. This constellation of peripherally generated signals has to be considered to understand how hormones,
neurotransmitters, and neuropeptides exert their regulatory
functions and serve to integrate different body systems.
As a consequence of local stimuli, changes in the functional
state of a cell could occur. Thus, when a given hormone or
neurotransmitter reaches this cell, its final effect would be
almost unpredictable and, therefore, difficult to control at
CNS levels. The brain would need accurate information
about peripheral events to monitor the efficiency of neuroendocrine regulatory mechanisms and to adjust the set point
for the regulation of certain variables during different stages
and conditions of life. As mentioned above, certain cytokines
could provide the information derived from immune cells.
However, at present there is not sufficient experimental evidence of the existence of retro-hormonal pathways to the
brain mediated by products released by other key peripheral
cells. One example of this type of messenger could be the
product of a recently cloned gene expressed specifically by
adipocytes which, as suggested by the authors, may affect
CNS structures that regulate the size of the body fat depot
(578). Although more direct evidence is necessary, this example may indicate that peripheral cells other than immunological and classic endocrine cells can also communicate
with the CNS.
89
Acknowledgments
We thank Dr. G. P. McGregor for reviewing the manuscript and
S. Petzoldt for editorial help.
References
1. Cake MH, Litwack G 1975 The glucocorticoid receptors. In:
Litwack G (ed) Biochemical Actions of Hormones. Academic Press,
New York, vol 3:317-390
2. Werb Z, Foley R, Munck A1978 Interaction of glucocorticoids with
macrophages. Identification of glucocorticoid receptors in monocytes and macrophages. J Exp Med 147:1684-1694
3. Helderman JH, Strom T1978 Specific insulin binding site on T and
B lymphocytes as a marker of cell activation. Nature 274:62-63
4. Hollenberg MD, Cuatrecasas P1974 Hormone receptors and membrane glycoproteins during in vitro transformation of lymphocytes.
In: Clarkson B, Baserga R (eds) Control of Proliferation of Animal
Cells. Cold Spring Harbor Laboratory, Cold Spring Harbor, New
York, pp 423-434
5. Hiestand P, Mekler P 1986 Mechanism of action: cyclosporin- and
prolactin-mediated control of immunity. Prog Allergy 38:239-246
6. Russell DH, Matrision L, Kibler R, Larson D, Poulps B, Magun
B 1984 Prolactin receptor on human lymphocytes and their modulation by cyclosporin. Biochem Biophys Res Commun 121:899906
7. Arrenbrecht S 1974 Specific binding of growth hormone to thymocytes. Nature 252:255-257
8. Gillette S, Gillette R 1979 Changes in thymic estrogen receptor
expression following orchidectomy. Cell Immunol 42:194-196
9. Abraham AD, Bug G 1976 3H-testosterone distribution and binding in rat thymus cells in vivo. Mol Cell Biochem 13:157-163
10. Bourne HR, Lichtenstein LM, Melmon KL, Henney CS,
Weinstein Y, Shearer GM 1974 Modulation of inflammation and
immunity by cyclic AMP. Receptors for vasoactive hormones and
mediators of inflammation regulate many leukocyte functions.
Science 184:19-28
11. Hadden JW, Hadden EM, Middleton EJ 1970 Lymphocyte blast
transformation. I. Demonstration of adrenergic receptors in human
peripheral lymphocytes. Cell Immunol 1:583-595
12. Landmann RMA, Bittiger H, Biihler FR 1981 High affinity beta2-adrenergic receptors in mononuclear leucocytes: similar density
in young and old normal subjects. Life Sci 29:1761-1771
13. Landmann RMA, Wesp M, Box R, Keller U, Biihler FR 1989
Distribution and function of /3-adrenergic receptors in human
blood lymphocytes. In: Hadden JW, Masek K, Nistico G (eds)
Interactions among CNS, Neuroendocrine and Immune systems.
Pythagora Press, Rome, pp 251-264
14. Singh U, Millson DS, Smith PA, Owen JJT 1979 Identification
of beta-adrenoceptors during thymocyte ontogeny in mice. Eur
J Immunol 9:31-35
15. Richman DP, Arnason BG 1979 Nicotinic acetylcholine receptor:
evidence for a functionally distinct receptor on human lymphocytes. Proc Natl Acad Sci USA 76:4632-4635
16. Strom TB, Sytkowkski AJ, Carpenter CB, Merrill JP 1974 Cholinergic augmentation of lymphocyte-mediated cytotoxicity. A
study of the cholinergic receptor of cytotoxic T lymphocytes. Proc
Natl Acad Sci USA 71:1330-1333
17. Hazum E, Chang KJ, Cuatrecasas P 1979 Specific nonopiate receptors for beta endorphins. Science 205:1033-1035
18. Wybran J, Appelboom T, Famaey JP, Govaerts A 1979 Suggestive
evidence for morphin and methionine-enkephalin receptor-like
structures on normal blood T lymphocytes. J Immunol 123:10681070
19. Payan D, Brewster D, Missirian-Bastian A, Goetzl E 1984 Substance P recognition by a subset of human T lymphocytes. J Clin
Invest 74:1532-1539
20. Stanisz A, Scicchitano R, Payan D, Bienenstock J 1987 In vitro
studies of immunoregulation by substance P and somatostatin.
Ann NY Acad Sci 496:217-225
21. Ottaway CA1991 Vasoactive intestinal peptide and immune function. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology,
ed 2. Academic Press Inc, New York, pp 225-262
90
BESEDOVSKY AND DEL REY
22. Dailey MO, Schreurs J, Schulman H 1988 Hormone receptors on
cloned T lymphocytes. Increased responsiveness to histamine,
prostaglandins and /3-adrenergic agents as a late stage in T cell
activation. J Immunol 140:2931-2936
23. Strom TB, Lane MA, George K1981 The parallel, time-dependent,
bimodal change in lymphocyte cholinergic binding activity and
cholinergic influence upon lymphocyte-mediated cytotoxicity after
lymphocyte activation. J Immunol 127:705-710
24. Smith KA, Crabtree GR, Kennedy SJ, Munck AU 1977 Glucocorticoid receptors and glucocorticoid sensitivity of mitogen stimulated and unstimulated human lymphocytes. Nature 267:523-525
25. De Souza EB, Webster EL, Grigoriadis DE, Tracey DE 1989 Corticotropin-releasing factor (CRF) and interleukin-1 (IL-1) receptors
in the brain-pituitary-immune axis. Psychopharmacol Bull 25:299305
26. Ban E, Milon G, Prudhomme N, Fillion G, Haour F1991 Receptors
for interleukin-1 (alpha and beta) in mouse brain: mapping and
neuronal localization in hippocampus. Neuroscience 43:21-30
27. Takao T, Culp SG, Newton RC, De Souza EB 1992 Type I interleukin-1 receptors in the mouse brain-endocrine-immune axis labelled with [1^5I]recombinant human interleukin-1 receptor antagonist. J Neuroimmunol 41:51-60
28. Cunningham JR ET, Wada E, Carter DB, Tracey DE, Battey JF, De
Souza EB 1992 In situ histochemical localization of type I interleukin-1 receptor messenger RNA in the central nervous system,
pituitary, and adrenal gland of the mouse. J Neurosci 12:1101-1114
29. Parnet P, Brunke DL, Goujon E, Mainard JD, Biragyn A, Arkins
S, Dantzer R, Kelley KW 1993 Molecular identification of two
types of interleukin-1 receptors in the murine pituitary gland.
J Neuroendocrinol 5:213-219
30. Kasai K, Hiraiwa M, Emoto T, Kuroda H, Hattori Y, Mochizuki
Y, Nakamura T, Shimoda S 1990 Presence of high affinity receptor
for interleukin-1 (IL-1) on cultured porcine thyroid cells. Horm
Metab Res 22:75-79
31. Svenson M, Kayser L, Hansen MB, Rasmussen AK, Bendtzen K
1991 Interleukin-1 receptors on human thyroid cells and on the rat
thyroid cell line FRTL-5. Cytokines 3:125-130
32. Deyerle KL, Sims JE, Dower SK, Bothwell MA 1992 Pattern of IL-1
receptor gene expression suggests role in noninflammatory processes. J Immunol 149:1657-1665
33. Hurwitz A, Loukides J, Ricciarelli E, Botero L, Katz E, McAllister
JM, Garcia JE, Rohan R, Adashi EY, Hernandez ER 1992 Human
intraovarian interleukin-1 (IL-1) system: highly compartmentalized and hormonally dependent regulation of the genes encoding
IL-1, its receptor, and its receptor antagonist. J Clin Invest 89:17461754
34. Simon C, Frances A, Piquette G, Polan ML 1994 Immunohistochemical localization of the interleukin-1 system in the mouse
ovary during follicular growth, ovulation, and luteinization. Biol
Reprod 50:449-457
35. Cunningham Jr ET, Wada E, Carter DB, Tracey DE, Battey JF, De
Souza EB 1992 Distribution of type I interleukin-1 receptor messenger RNA in testis: an in situ histochemical study in the mouse.
Neuroendocrinology 56:94-99
36. Smith LR, Brown SL, Blalock JE 1989 Interleukin-2 induction of
ACTH secretion: presence of an interleukin-2 receptor alpha-chainlike molecule on pituitary cells. J Neuroimmunol 21:249-254
37. Arzt E, Stelzer G, Renner U, Lange M, Muller OA, Stalla GK1992
Interleukin-2 and interleukin-2 receptor expression in human corticotrophic adenoma and murine pituitary cell cultures. J Clin
Invest 90:1944-1951
38. Knoop M, McMahon RF, Hutchinson IV 1990 Staining of native
and grafted exocrine rat pancreas by an interleukin-2 receptor
specific monoclonal antibody. Acta Histochem 88:51-52
39. Ohmichi M, Hirota K, Koike K, Kurachi H, Ohtsuka S, Matsuzaki
N, Yamaguchi M, Miyake A, Tanizawa O 1992 Binding sites for
interleukin-6 in the anterior pituitary gland. Neuroendocrinology
55:199-203
40. Winter JS, Gow KW, Perry YS, Greenberg AH 1990 A stimulatory
effect of interleukin-1 on adrenocortical cortisol secretion mediated
by prostaglandins. Endocrinology 127:1904-1909
41. Yanagihara N, Minami K, Shirakawa F, Uezono Y, Kobayashi H,
Eto S, Izumi F1994 Stimulatory effect of IL-1 beta on catecholamine
42.
43.
44.
45.
46.
47.
Vol. 17, No. 1
secretion from cultured bovine adrenal medullary cells. Biochem
Biophys Res Commun 198:81-87
Farrar WL, Kilian PL, Ruff MR, Hill JM, Pert CB 1987 Visualization and characterization of interleukin 1 receptors in brain. J Immunol 139:459-463
Hill JM, Lesniak MA, Pert CB 1988 Co-localization of IGF-II
receptors, IL-1 receptors and Thy 1.1 in rat brain. Peptides 9
[Suppl l]:91-96
Katsuura G, Gottschall PE, Arimura A 1988 Identification of a
high-affinity receptor for interleukin-1 beta in rat brain. Biochem
Biophys Res Commun 156:61-67
Cunningham Jr ET, Wada E, Carter DB, Tracey DE, Battey JF, De
Souza EB 1991 Localization of interleukin-1 receptor messenger
RNA in murine hippocampus. Endocrinology 128:2666-2668
Takao T, Culp SG, De Souza EB 1993 Reciprocal modulation of
interleukin-1 beta (IL-1 beta) and IL-1 receptors by lipopolysaccharide (endotoxin) treatment in the mouse brain-endocrineimmune axis. Endocrinology 132:1497-1504
Marquette C, Van Dam AM, Van Rooijen N, Berkenbosch F,
Haour F 1994 Peripheral macrophage depletion prevents down
regulation of central interleukin-1 receptors in mice after endotoxin
administration. Psychoneuroendocrinology 19:189-196
48. Reinisch N, Wolkersdorfer M, Kahler CM, Ye K, Dinarello CA,
Wiedermann CJ1994 Interleukin-1 receptor type I mRNA in mouse
brain as affected by peripheral administration of bacterial lipopolysaccharide. Neurosci Lett 166:165-167
49. Ban E, Marquette C, Sarrieau A, Fitzpatrick F, Fillion G, Milon
G, Rostene W, Haour F 1993 Regulation of interleukin-1 receptor
expression in mouse brain and pituitary by lipopolysaccharide and
glucocorticoids. Neuroendocrinology 58:581-587
50. De Souza EB 1993 Corticotropin-releasing factor and interleukin-1
receptors in the brain-endocrine-immune axis. Role in stress response and infection. Ann NY Acad Sci 697:9-27
51. Tada M, Diserens AC, Desbaillets I, de Tribolet N 1994 Analysis
of cytokine receptor messenger RNA expression in human glioblastoma cells and normal astrocytes by reverse-transcription polymerase chain reaction. J Neurosurg 80:1063-1073
52. Araujo DM, Lapchak PA, Collier B, Quirion R 1989 Localization
of interleukin-2 immunoreactivity and interleukin-2 receptors in
the rat brain: interaction with the cholinergic system. Brain Res
498:257-266
53. Lapchak PA, Araujo DM, Quirion R, Beaudet A 1991 Immunoautoradiographic localization of interleukin 2-like immunoreactivity and interleukin 2 receptors (Tac antigen-like immunoreactivity)
in the rat brain. Neuroscience 44:173-184
54. Lowenthal JW, Castle BE, Christiansen J, Schreurs J, Rennick D,
Arai N, Hoy P, Takebe Y, Howard M 1988 Expression of high
affinity receptors for murine interleukin 4 (BSF-1) on hemopoietic
and nonhemopoietic cells. J Immunol 140:456-464
55. Cornfield LJ, Sills MA 1991 High affinity interleukin-6 binding
sites in bovine hypothalamus. Eur J Pharmacol 202:113-115
56. Schobitz B, Voorhuis DA, De Kloet ER 1992 Localization of interleukin 6 mRNA and interleukin 6 receptor mRNA in rat brain.
Neurosci Lett 136:189-192
57. Gadient RA, Otten U 1993 Differential expression of interleukin-6
(IL-6) and interleukin-6 receptor (IL-6R) mRNAs in rat hypothalamus. Neurosci Lett 153:13-16
58. Gadient RA, Otten U 1994 Expression of interleukin-6 (IL-6) and
interleukin-6 receptor (IL-6R) mRNAs in rat brain during postnatal
development. Brain Res 637:10-14
59. Schobitz B, de Kloet ER, Sutanto W, Holsboer F 1993 Cellular
localization of interleukin 6 mRNA and interleukin 6 receptor
mRNA in rat brain. Eur J Neurosci 5:1426-1435
60. Kinouchi K, Brown G, Pasternak G, Donner DB 1991 Identification and characterization of receptors for tumor necrosis factoralpha in the brain. Biochem Biophys Res Commun 18:1532-1538
61. Wolvers DA, Marquette C, Berkenbosch F, Haour F 1993 Tumor
necrosis factor-alpha: specific binding sites in rodent brain and
pituitary gland. Eur Cytokine Netw 4:377-381
62. Chang Y, Albright S, Lee F 1994 Cytokines in the central nervous
system: expression of macrophage colony stimulating factor and its
receptor during development. J Neuroimmunol 52:9-17
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
63. Bulloch K, Moore RY1981 Innervation of the tymus gland by brain
stem and spinal cord in mouse and rat. Am J Anat 162:157-166
64. Reilly FD, McCuskey RA, Miller ML, McCuskey RS, Meineke
HA 1979 Innervation of the periarteriolar lymphatic sheath of the
spleen. Tissue Cell 11:121-126
65. Williams JM, Felten DL 1981 Sympathetic innervation of murine
thymus and spleen: a comparative histofluorescence study. Anat
Rec 199:531-542
66. Weihe E 1991 Molecular anatomy of the neuroimmune communication. Int J Neurosci 59:1-23
67. Payan DG, Levine JD, Goetzl EJ1984 Modulation of immunity and
hypersensitivity by sensory neuropeptides. J Immunol 132:16011604
68. Smith EM, Blalock JE 1981 Human lymphocyte production of
ACTH and endorphin-like substances. Association with leukocyte
interferon. Proc Natl Acad Sci USA 78:7530-7534
69. Smith EM, Galin S, Le Boeuf RD, Coppenhaver DH, Harbour
DH, Blalock JE 1990 Nucleotide and amino acid sequence of lymphocyte-derived corticotropin: endotoxin induction of a truncated
peptide. Proc Natl Acad Sci USA 87:1057-1060
70. Sharp B, Linner K 1993 What do we know about the expression of
proopiomelanocortin transcripts and related peptides in lymphoid
tissues? Endocrinology 133:1921-1922
71. Dunn A, Powell ML, Gaskin JM 1987 Virus-induced increases in
plasma corticosterone. Science 238:1423-1425
72. Olsen NJ, Nicholson WE, DeBold CR, Orth DN1992 Lymphocytederived adrenocorticotropin is insufficient to stimulate adrenal
steroidogenesis in hypophysectomized rats. Endocrinology 130:
2113-2119
73. Mechanick JI, Levin N, Roberts JL, Autelitano DJ 1992 Proopiomelanocortin gene expression in a distinct population of rat spleen
and lung leukocytes. Endocrinology 131:518-525
74. Hiestand PC, Mekler P, Nordmann R, Grieder A, Permmongkol
C 1986 Prolactin as a modulator of lymphocyte responsiveness
provides a possible mechanism of action for cyclosporin. Proc Natl
Acad Sci USA 83:2599-2603
75. Carr DJJ, Weigent DA, Blalock JE 1989 Hormones common to the
neuroendocrine and immune systems. Drug Des Deliv 4:187-195
76. Cutz E, Chan W, Track NS, Goth A, Said SI 1978 Release of
vasoactive intestinal polypeptide in mast cells by histamine liberators. Nature 275:661-662
77. Weinstock JV1988 Tachykin production by granuloma eosinophils
in murine Schistosomiasis mansoni. In: MacDermott RP (ed) Inflammatory Bowel Disease: Current Status and Future Approach.
Elsevier, Amsterdam, pp 335-341
78. Vankelecom H, Carmeliet P, Van Damme J, Billiau A, Denef C
1989 Production of interleukin-6 by folliculo-stellate cells of the
anterior pituitary gland in a histiotypic cell aggregate culture system. Neuroendocrinology 49:102-106
79. Yamaguchi M, Matsuzaki N, Hirota K, Miyake A, Tanizawa O
1990 Interleukin 6 possibly induced by interleukin 1 beta in the
pituitary gland stimulates the release of gonadotropins and prolactin. Acta Endocrinol (Copenh) 122:201-205
80. Spangelo BL, Judd AM, MacLeod RM, Goodman DW, Isakson
PC 1990 Endotoxin-induced release of interleukin-6 from rat medial basal hypothalami. Endocrinology 127:1779-1785
81. Spangelo BL, MacLeod RM, Isakson PC 1991 Production of interleukin-6 by anterior pituitary cells in vitro. Endocrinology 126:
582-586
82. Spangelo BL, Judd AM, Isakson PC, MacLeod RM 1991 Interleukin-1 stimulates interleukin-6 release from rat anterior pituitary
cells in vitro. Endocrinology 128:2685-2692
83. Schobitz B, Holsboer F, Kikkert R, Sutanto W, De Kloet ER1992
Peripheral and central regulation of IL-6 gene expression in endotoxin-treated rats. Endocr Regul 26:103-109
84. Schobitz B, Van Den Dobbelsteen M, Holsboer F, Sutanto W, De
Kloet ER 1993 Regulation of interleukin 6 gene expression in rat.
Endocrinology 132:1569-1576
85. Velkeniers B, Vergani P, Trouillas J, D'Haens J, Hooghe RJ,
Hooghe Peters EL 1994 Expression of IL-6 mRNA in normal rat and
human pituitaries and in human pituitary adenomas. J Histochem
Cytochem 42:67-76
86. Muramami N, Fukata J, Tsukada T, Kobayashi H, Ebisui O,
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
91
Segawa H, Muro S, Imura H, Nakao K1993 Bacterial lipopolysaccharide-induced expression of interleukin-6 messenger ribonucleic
acid in the rat hypothalamus, pituitary, adrenal gland, and spleen.
Endocrinology 133:2574-2578
Yamaguchi M, Koike K, Matsuzaki N, Yoshimoto Y, Taniguchi
T, Miyake A, Tanizawa 01991 The interferon family stimulates the
secretions of prolactin and interleukin-6 by the pituitary gland in
vitro. J Endocrinol Invest 14:457-461
Spangelo BL, Jarvis WD, Judd AM, MacLeod RM 1991 Induction
of interleukin-6 release by interleukin-1 in rat anterior pituitary
cells in vitro: evidence for an eicosanoid-dependent mechanism.
Endocrinology 129:2886-2894
Nash AD, Brandon MR, Bello PA 1992 Effects of tumour necrosis
factor-alpha on growth hormone and interleukin 6 mRNA in ovine
pituitary cells. Mol Cell Endocrinol 84:R31-R37
Tatsuno I, Somogyvari Vigh A, Mizuno K, Gottschall PE, Hidaka
H, Arimura A 1991 Neuropeptide regulation of interleukin-6 production from the pituitary: stimulation by pituitary adenylate cyclase activating polypeptide and calcitonin gene-related peptide.
Endocrinology 129:1797-1804
Carmeliet P, Vankelecom H, Van Damme J, Billiau A, Denef C
1991 Release of interleukin-6 from anterior pituitary cell aggregates: developmental pattern and modulation by glucocorticoids
and forskolin. Neuroendocrinology 53:29-34
Sarlis NJ, Stephanou A, Knight RA, Lightman SL, Chowdrey HS
1993 Effects of glucocorticoids and chronic inflammatory stress
upon anterior pituitary interleukin-6 mRNA expression in the rat.
Br J Rheumatol 32:653-657
Vankelecom H, Matthys P, Van Damme J, Heremans H, Billiau
A, Denef C1993 Immunocytochemical evidence that S-100-positive
cells of the mouse anterior pituitary contain interleukin-6 immunoreactivity. J Histochem Cytochem 41:151-156
Spangelo BL, deHoll PD, Kalabay L, Bond BR, Arnaud P 1994
Neurointermediate pituitary lobe cells synthesize and release interleukin-6 in vitro: effects of lipopolysaccharide and interleukin-1
beta. Endocrinology 135:556-563
Koenig JI, Snow K, Clark BD, Toni R, Cannon JG, Shaw AR,
Dinarello CA, Reichlin S, Lee SL, Lechan RM 1990 Intrinsic pituitary interleukin-1 beta is induced by bacterial lipopolysaccharide. Endocrinology 126:3053-3058
Gatti S, Bartfai T 1993 Induction of tumor necrosis factor-alpha
mRNA in the brain after peripheral endotoxin treatment: comparison with interleukin-1 family and interleukin-6. Brain Res 624:
291-294
Koike K, Sakamoto Y, Sawada T, Ohmichi M, Kanda Y, Nohara
A, Hirota K, Kiyama H, Miyake A 1994 The production of CINC/
gro, a member of the interleukin-8 family, in rat anterior pituitary
gland. Biochem Biophys Res Commun 202:161-167
Schultzberg M, Andersson C, Unden A, Troye Blomberg M,
Svenson SB, Bartfai T 1989 Interleukin-1 in adrenal chromaffin
cells. Neuroscience 30:805-810
Judd AM, MacLeod RM 1992 Adrenocorticotropin increases interleukin-6 release from rat adrenal zona glomerulosa cells. Endocrinology 130:1245-1254
Jaattela M, Carpen O, Stenman UH, Saksela E 1990 Regulation of
ACTH-induced steroidogenesis in human fetal adrenals by rTNFalpha. Mol Cell Endocrinol 68:R31-R36
Yamada K, Takane N, Otabe S, Inada C, Inoue M, Nonaka K1993
Pancreatic beta-cell-selective production of tumor necrosis factoralpha induced by interleukin-1. Diabetes 42:1026-1031
Khan SA, Soder O, Syed V, Gustafsson K, Lindh M, Ritzen EM
1987 The rat testis produces large amounts of an interleukin-1-like
factor. Int J Androl 10:495-503
Gustafsson K, Soder O, Pollanen P, Ritzen EM 1988 Isolation and
partial characterization of an interleukin-1-like factor from rat testis
interstitial fluid. J Reprod Immunol 14:139-150
Khan SA, Schmidt K, Hallin P, Di Pauli R, De Geyter C,
Nieschlag E1988 Human testis cytosol and ovarian follicular fluid
contain high amounts of interleukin-1-like factor(s). Mol Cell
Pollanen P, von Euler M, Soder O 1990 Testicular immunoregulatory factors. J Reprod Immunol 18:51-76
Gerard N, Syed V, Bardin W, Genetet N, Jegou B1991 Sertoli cells
92
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
BESEDOVSKY AND DEL REY
are the site of interleukin-1 alpha synthesis in rat testis. Mol Cell
Endocrinol 82:R13-R16
Lin T, Wang D, Nagpal ML 1993 Human chorionic gonadotropin
induces interleukin-1 gene expression in rat Leydig cells in vivo.
Mol Cell Endocrinol 95:139-145
De SK, Chen HL, Pace JL, Hunt JS, Terranova PF, Enders GC1993
Expression of tumor necrosis factor-alpha in mouse spermatogenic
cells. Endocrinology 133:389-396
Hutson JC 1993 Secretion of tumor necrosis factor alpha by testicular macrophages. J Reprod Immunol 23:63-72
Moore C, Hutson JC 1994 Physiological relevance of tumor necrosis factor in mediating macrophage-Leydig cell interactions.
Endocrinology 134:63-69
Xiong Y, Hales DB 1993 Expression, regulation, and production of
tumor necrosis factor-alpha in mouse testicular interstitial macrophages in vitro. Endocrinology 133:2568-2573
De SK, McMaster MT, Andrews GK 1990 Endotoxin induction of
murine metallothionein gene expression. J Biol Chem 265:1526715274
Hurwitz A, Ricciarelli E, Botero L, Rohan RM, Hernandez ER,
Adashi EY 1991 Endocrine- and autocrine-mediated regulation of
rat ovarian (theca-interstitial) interleukin-1 beta gene expression:
gonadotropin-dependent preovulatory acquisition. Endocrinology
129:3427-3429
Barak V, Yanai P, Treves AJ, Roisman I, Simon A, Laufer N 1992
Interleukin-1: local production and modulation of human granulosa luteal cells steroidogenesis. Fertil Steril 58:719-725
Polan ML, Loukides JA, Honig J 1994 Interleukin-1 in human
ovarian cells and in peripheral blood monocytes increases during
the luteal phase: evidence for a midcycle surge in the human. Am
J Obstet Gynecol 170:1000-1006
Ziltener HJ, Maines Bandiera S, Schrader JW, Auersperg N 1993
Secretion of bioactive interleukin-1, interleukin-6, and colony-stimulating factors by human ovarian surface epithelium. Biol Reprod
49:635-641
Motro B, Itin A, Sachs L, Keshet E 1990 Pattern of interleukin 6
gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci USA 87:3092-3096
Brannstrom M, Norman RJ, Seamark RF, Robertson SA 1994 Rat
ovary produces cytokines during ovulation. Biol Reprod 50:88-94
Roby KF, Weed J, Lyles R, Terranova PF 1990 Immunological
evidence for a human ovarian tumor necrosis factor-alpha. J Clin
Endocrinol Metab 71:1096-1102
Wang LJ, Brannstrom M, Robertson SA, Norman RJ 1992 Tumor
necrosis factor alpha in the human ovary: presence in follicular
fluid and effects on cell proliferation and prostaglandin production. Fertil Steril 58:934-940
Sancho Tello M, Perez Roger I, Imakawa K, Tilzer L, Terranova
PF 1992 Expression of tumor necrosis factor-alpha in the rat ovary.
Endocrinology 130:1359-1364
Chen HL, Marcinkiewicz JL, Sancho Tello M, Hunt JS, Terranova
PF 1993 Tumor necrosis factor-alpha gene expression in mouse
oocytes and follicular cells. Biol Reprod 48:707-714
Fontana A, Kristensen F, Dubs R, Gemsa D, Weber E 1982 Production of prostaglandin E and interleukin 1-like factors by cultured astrocytes and C-6 glioma cells. J Immunol 129:2413-2419
Fabry Z, Raine CS, Hart MN 1994 Nervous tissue as an immune
compartment: the dialect of the immune response in the CNS.
Immunol Today 15:218-224
Bandtlow CE, Meyer M, Lindholm D, Spranger M, Heumann R,
Thoenen H1990 Regional and cellular codistribution of interleukin
1 beta and nerve growth factor mRNA in the adult rat brain:
possible relationship to the regulation of nerve growth factor synthesis. J Cell Biol 111:1701-1711
Minami M, Kuraishi Y, Yamaguchi T, Nakai S, Hirai Y, Satoh M
1990 Convulsants induce interleukin-1 beta messenger RNA in rat
brain. Biochem Biophys Res Commun 171:832-837
Lechan RM, Toni R, Clark BD, Cannon JG, Shaw AR, Dinarello
CA, Reichlin S 1990 Immunoreactive interleukin-1 beta localization in the rat forebrain. Brain Res 514:135-140
Yamaguchi T, Kuraishi Y, Minami M, Nakai S, Hirai K, Satoh M
1991 Methamphetamine-induced expression of IL-1/3 mRNA in the
rat hypothalamus. Neurosci Lett 128:90-92
Vol. 17, No. 1
129. Higgins GA, Olschowka JA 1991 Induction of interleukin-1 beta
mRNA in adult rat brain. Brain Res Mol Brain Res 9:143-148
130. Minami M, Kuraishi Y, Yamaguchi T, Nakai S, Hirai Y, Satoh M
1991 Immobilization stress induces interleukin-1 beta mRNA in the
rat hypothalamus. Neurosci Lett 123:254-256
131. Granholm T, Froysa B, Midtvedt T, Soder O 1992 Ontogeny of
lymphocyte activating factors in conventional and germfree rats.
Reg Immunol 4:209-215
132. Van Dam AM, Brouns M, Louisse S, Berkenbosch F 1992 Appearance of interleukin-1 in macrophages and in ramified microglia
in the brain of endotoxin-treated rats: a pathway for the induction
of non-specific symptoms of sickness? Brain Res 588:291-296
133. Minami M, Kuraishi Y, Yabuuchi K, Yamazaki A, Satoh M 1992
Induction of interleukin-1 beta mRNA in rat brain after transient
forebrain ischemia. J Neurochem 58:390-392
134. Hillhouse EW, Mosley K 1993 Peripheral endotoxin induces hypothalamic immunoreactive interleukin-1 beta in the rat. BrJ Pharmacol 109:289-290
135. Quan N, Sundar SK, Weiss JM 1994 Induction of interleukin-1 in
various brain regions after peripheral and central injections of
lipopolysaccharide. J Neuroimmunol 49:125-134
136. Yabuuchi K, Minami M, Katsumata S, Satoh M 1993 In situ hybridization study of interleukin-1 beta mRNA induced by kainic
acid in the rat brain. Brain Res Mol Brain Res 20:153-161
137. Minami M, Kuraishi Y, Satoh M 1991 Effects of kainic acid on
messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the
rat brain. Biochem Biophys Res Commun 176:593-598
138. Hagan P, Poole S, Bristow AF1993 Endotoxin-stimulated production of rat hypothalamic interleukin-1 beta in vivo and in vitro,
measured by specific immunoradiometric assay. J Mol Endocrinol
11:31-36
139. Ban E, Haour F, Lenstra R1992 Brain interleukin 1 gene expression
induced by peripheral lipopolysaccharide administration. Cytokines 4:48-54
140. Tchelingerian JL, Quinonero J, Booss J, Jacque C 1993 Localization of TNFa and IL-la immunoreactivities in striatal neurons after
surgical injury in the hippocampus. Neuron 10:213-224
141. Nakamori T, Morimoto A, Yamaguchi K, Watanabe T, Long NC,
Murakami N 1993 Organum vasculosum laminae terminalis
(OVLT) is a brain site to produce interleukin-1 beta during fever.
Brain Res 618:155-159
142. Clark BD, Bedrosian I, Schindler R, Cominelli F, Cannon JG,
Shaw AR, Dinarello CA 1991 Detection of interleukin 1 alpha and
1 beta in rabbit tissues during endotoxemia using sensitive radioimmunoassays. J Appl Physiol 71:2412-2418
143. Molenaar G, Berkenbosch F, van Damm AM, Lugard CMJE 1993
Distribution of IL-1/3 immunoreactivity within the porcine hypothalamus. Brain Res 608:169-174
144. Coceani F, Lees J, Dinarello CA 1988 Occurrence of interleukin-1
in cerebrospinal fluid of the conscious cat. Brain Res 446:245-250
145. Breder CD, Dinarello CA, Saper CB 1988 Interleukin-1 immunoreactive interaction of the human hypothalamus. Science 240:321323
146. Licinio J, Wong ML, Gold PW 1991 Localization of interleukin-1
receptor antagonist mRNA in rat brain. Endocrinology 129:562-564
147. Farrar WL, Vinocour M, Hill JM 1989 In situ hybridization histochemistry localization of interleukin-3 mRNA in mouse brain.
Blood 73:137-140
148. LeMay LG, Otterness IG, Vander AJ, Kluger MJ 1990 In vivo
evidence that the rise in plasma IL 6 following injection of a feverinducing dose of LPS is mediated by IL 1 beta. Cytokines 2:199-204
149. Klir JJ, McClellan JL, Kluger MJ 1994 Interleukin-1 beta causes the
increase in anterior hypothalamic interleukin-6 during LPS-induced fever in rats. Am J Physiol 266:R1845-R1848
150. Kiefer R, Lindholm D, Kreutzberg GW 1993 Interleukin-6 and
transforming growth factor-beta 1 mRNAs are induced in rat facial
nucleus following motoneuron axotomy. Eur J Neurosci 5:775-781
151. Burns TM, Clough JA, Klein RM, Wood GW, Berman NE 1993
Developmental regulation of cytokine expression in the mouse
brain. Growth Factors 9:253-258
152. Licinio J, Wong ML, Gold PW 1992 Neutrophil-activating peptidel/interleukin-8 mRNA is localized in rat hypothalamus and hippocampus. Neuroreport 3:753-756
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
153. Schoenhaut DS, Chua AO, Wolitzky AG, Quinn PM, Dwyer CM,
McComas W, Familletti PC, Gately MK, Gubler U 1992 Cloning
and expression of murine IL-12. J Immunol 148:3433-3440
154. Hallenbeck JM, Dutka AJ, Vogel SN, Heldman E, Doron DA,
Feuerstein G 1991 Lipopolysaccharide-induced production of tumor necrosis factor activity in rats with and without risk factors for
stroke. Brain Res 541:115-120
155. Siren AL, Liu Y, Feuerstein G, Hallenbeck JM 1993 Increased
release of tumor necrosis factor-alpha into the cerebrospinal fluid
and peripheral circulation of aged rats. Stroke 24:880-886
156. Breder CD, Dinarello CA, Saper CB 1988 Interleukin-1 immunoreactive innervation of the human hypothalamus. Science 240:321324
157. Gendron RL, Nestel FP, Lapp WS, Baines MG 1991 Expression of
tumor necrosis factor alpha in the developing nervous system. Int
J Neurosci 60:129-136
158. Tarlow MJ, Jenkins R, Comis SD, Osborne MP, Stephens S,
Stanley P, Crocker J 1993 Ependymal cells of the choroid plexus
express tumour necrosis factor-alpha. Neuropathol Appl Neurobiol 19:324-328
159. Ljungdahl A, Olsson T, Van der Meide PH, Holmdahl R, Klareskog L, Hojeberg B 1989 Interferon-gamma-like immunoreactivity
in certain neurons of the central and peripheral nervous system.
J Neurosci Res 24:451-456
160. Olsson T, Kristensson K, Ljungdahl A, Maehlen J, Holmdahl R,
Klareskog L1989 Gamma-interferon-like immunoreactivity in axotomized rat motor neurons. J Neurosci 9:3870-3875
161. Nohava K, Malipiero U, Frei K, Fontana A 1992 Neurons and
neuroblastoma as a source of macrophage colony-stimulating factor. Eur J Immunol 22:2539-2545
162. Da Cunha A, Vitkovic L 1992 Transforming growth factor-beta 1
(TGF-beta 1) expression and regulation in rat cortical astrocytes.
J Neuroimmunol 36:157-169
163. Lustig S, Danenberg HD, Kafri Y, Kobiler D, Ben-Nathan D 1992
Viral neuroinvasion and encephalitis induced by lipopolysaccharide and its mediators. J Exp Med 176:707-712
164. Kiefer R, Kreutzberg GW 1990 Gamma interferon-like immunoreactivity in the rat nervous system. Neuroscience 37:725-734
165. Kiefer R, Haas CA, Kreutzberg GW 1991 Gamma interferon-like
immunoreactive material in rat neurons: evidence against a close
relationship to gamma interferon. Neuroscience 45:551-560
166. Andersson C, Svenson SB, Van Deventer S, Cerami A, Bartfai T
1992 lnterleukin-1 alpha expression is inducible by cholinergic
stimulation in the rat adrenal gland. Neuroscience 47:481-485
167. Freidin M, Bennett MV, Kessler JA 1992 Cultured sympathetic
neurons synthetize and release the cytokine interleukin 1. Proc Natl
Acad Sci USA 89:10440-10443
168. Munck A, Guyre PM 1991 Glucocorticoids and immune function.
In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed
2. Academic Press Inc, New York, pp 447-513
169. Bateman A, Singh A, Krai T, Solomon S 1989 The immunehypothalamic-pituitary-adrenal axis. Endocr Rev 10:92-111
170. Grossman CJ1984 Regulation of the immune system by sex steroid.
Endocr Rev 5:435-454
171. Kincade PW, Medina KL, Smithson G, Scott DC 1994 Pregnancy:
a clue to normal regulation of B lymphopoiesis. Immunol Today
15:539-541
172. Clarke AG, Kendall MD 1994 The thymus in pregnancy: the interplay of neural, endocrine and immune influences. Immunol
Today 15:545-551
173. McCruden AB, Stimson WH 1991 Sex hormones and immune
function. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 475-493
174. Johnson HM, Smith EM, Torres BA, Blalock JE 1982 Regulation
of the in vitro antibody response by neuroendocrine hormones. Proc
Natl Acad Sci USA 79:4171-4174
175. Berczi 11994 The role of the growth and lactogenic hormone family
in immune function. Neuroimmunomodulation 1:201-216
176. Kelley KW 1991 Growth hormone in immunobiology. In: Ader R,
Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic
Press Inc, New York, pp 377-402
177. Berton EW, Bryant HU, Holaday JW 1991 Prolactin and immune
93
function. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 403-428
178. Fabris N, Mocchegiani E, Mariotti S, Pacini F, Pinchera A 1989
Thyroid-thymus interactions during development and aging.
Horm Res 31:85-89
179. Snow EC 1985 Insulin and growth hormone function as minor
growth factors that potentiate lymphocyte activation. J Immunol
135:776s-778s
180. Homo-Delarche F, Durant S 1994 Hormones neurotransmitters
and neuropeptides as modulators of lymphocyte functions. In:
Rola-Pleszczynski M (ed) Immunopharmacology of Lymphocytes.
Academic Press Limited, London, pp 169-240
181. Talal N, Ansar Ahmed S 1987 Sex hormones and autoimmune
diseases: a short review. Int J Immunother 3:65-70
182. Plotnikoff NP, Faith RE, Murgo AJ, Good A (eds) 1986 Enkephalins and Endorphins. Stress and the Immune System. Plenum Press,
New York
183. Berczi I, Nagy E 1991 Effects of hypophysectomy on immune
function. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 339-375
184. Nagy E, Berczi I, Wren GE, Asa SL, Kovacs K 1983 Immunomodulation by bromocriptine. Immunopharmacology 6:321-243
185. Hartmann DP, Holaday JW, Bernton EW 1989 Inhibition of lymphocyte proliferation by antibodies to prolactin. FASEB J 3:21942202
186. Kelley KW, Brief S, Westly HJ, Novakofski J, Bechtel PJ, Simon
J, Walker E 1986 GH3 pituitary adenoma cells can reverse thymic
aging in rats. Proc Natl Acad Sci USA 83:5663-5667
187. Alvarez-Mon M, Kehrl JH, Fauci AS 1985 A potential role for
adrenocorticotropin regulatin human B lymphocyte functions.
J Immunol 135:3823-3826
188. del Rey A, Besedovsky HO, Sorkin E 1984 Endogenous blood
levels of corticosterone control the immunological cell mass and B
cell activity in mice. J Immunol 133:572-575
189. Galant SP, Remo RA 1975 Beta-adrenergic inhibition of human T
lymphocyte rosettes. J Immunol 114:512-513
190. Hammerling U, Chin AF, Abbott J, Scheid MP 1975 The ontogeny
of murine beta-lymphocytes. I. Induction of phenotypic conversion
of l a - to Ia+ lymphocytes. J Immunol 115:1425-1431
191. Henney CS, Bourne HR, Lichtenstein LM 1972 The role of cyclic
3,5'-adenosine monophosphate in the specific cytolytic activity of
lymphocytes. J Immunol 108:1526-1534
192. Ito M, Sless F, Parrott DMV 1977 Evidence for control of complement receptor rosette-forming cells by alpha- and beta-adrenergic agents. Nature 266:633-635
193. MacManus JP, Boynton AL, Whitfield JF, Gillan DJ, Isaacs RJ
1975 Acetylcholine-induced initiation of the thymic lymphoblast
DNA synthesis and proliferation. J Cell Physiol 85:321-330
194. Strom TB, Deisseroth A, Morgan-Roth J, Carpenter CB, Merrill
JP 1972 Alteration of the cytotoxic action of sensitized lymphocytes
by cholinergic agents and activators of adenylate cyclase. Proc Natl
Acad Sci USA 69:2995-2999
195. Besedovsky HO, del Rey A, Sorkin E, Da Prada M, Keller HA 1979
Immunoregulation mediated by the sympathetic nervous system.
Cell Immunol 48:346-355
196. Miles L, Quintans J, Chelmicka-Schorr E, Arnason EGW1981 The
sympathetic nervous system modulates antibody response to thymus-independent antigens. J Neuroimmunol 1:101-105
197. Hall NR, McClure JE, Hu SK, Tare NS, Seals CM, Goldstein AL
1982 Effects of 6-hydroxydopamine upon primary and secondary
thymus dependent immune responses. Immunopharmacology
5:39-48
198. Kasahara K, Tanaka S, Ito T, Hamashima Y 1977 Suppression of
the primary immune response by chemical sympathectomy. Res
Commun Chem Pathol Pharmacol 16:687-694
199. Livnat S, Felten SY, Carlson SL, Bellinger DL, Felten DL 1985
Involvement of peripheral and central catecholamine systems in
neural-immune interactions. J Neuroimmunol 10:5-30
200. Besedovsky HO, del Rey A1992 Immune-neuroendocrine circuits:
integrative role of cytokines. Front Neuroendocrinol 13:61-94
201. Marat BA 1974 Effect of central cholinolytics on the primary immune response in rabbits. Bull Exp Biol Med 76:971-973
202. Rinner I, Schauenstein K 1991 The parasympathetic nervous sys-
94
BESEDOVSKY AND DEL REY
tern takes part in the immuno-neuroendocrine dialogue. J Neuroimmunol 34:165-172
203. Stanisz AM, Befus D, Bienenstock J 1986 Differential effects of
vasoactive intestinal peptide, substance P, and somatostatin on
immunoglobulin synthesis and proliferations by lymphocytes from
Peyer's patches, mesenteric lymph nodes, and spleen. J Immunol
136:152-156
204. Ottaway CA 1987 Selective effects of vasoactive intestinal peptide
on the mitogenic response of murine T cells. Immunology 62:291297
205. Church MK, Lowman MA, Robinson C, Holgate ST, Benyon RC
1989 Interaction of neuropeptides with human mast cells. Int Arch
Allergy Appl Immunol 88:70-78
206. Eglezos A, Andrews PV, Boyd RL, Helme RD 1991 Tachykininmediated modulation of the primary antibody response in rats:
evidence for mediation by an NK-2 receptor. J Neuroimmunol
32:11-18
207. Scicchitano R, Bienenstock J, Stanisz AM 1988 In vivo immunomodulation by the neuropeptide substance P. Immunology 63:733735
208. Ijaz MK, Dent D, Babiuk LA 1990 Neuroimmuno-modulation of
in vivo anti-rotavirus humoral immune response. J Neuroimmunol
26:159-171
209. O'Dorisio MS, Hermina NS, O'Dorisio TM, Balcerzak SP 1981
Vasoactive intestinal polypeptide modulation of lymphocyte adenylate cyclase. J Immunol 127:2551-2554
210. Eglezos A, Andrews PV, Helme RD 1993 In vivo inhibition of the
rat primary antibody response to antigenic stimulation by somatostatin. Immunol Cell Biol 71:125-129
211. Payan DG, Hess CA, Goetzl EJ 1984 Inhibition by somatostatin of
the proliferation of T lymphocytes and Molt-4 lymphoblasts. Cell
Immunol 84:433-438
212. Jankovic BD, Isakovic K 1973 Neuro-endocrine correlations of
immune response. I. Effects of brain lesions on antibody production, Arthus reactivity and delayed hypersensitivity in the rat. Int
Arch Allergy Appl Immunol 45:360-372
213. Korneva EA, Khai LM 1963 Influence of hypothalamic part destruction on the immunogenesis process [in Russian]. Fiziol J SSSR
49:42-48
214. Roszman TL, Cross RJ, Brooks WH, Markesbery WR 1985 Neuroimmunomodulation: effects of neural lesions on cellular immunity. In: Guillemin R, Cohn M, Melnechuk T (eds) Neural Modulation of Immunity. Raven Press, New York, pp 95-109
215. Spector NH 1980 The central stage of the hypothalamus in health
and disease: old and new concepts. In: Morgane PJ, Panksepp J
(eds) Physiology of the Hypothalamus, Handbook of the Hypothalamus. Marcel Dekker, New York, vol 2:453-517
216. Stein M, Schiavi PC, Camerino M 1976 Influence of brain and
behavior of the immune system. Science 191:435-440
217. Monjan AA, Collector MI 1977 Stress-induced modulation of the
immune response. Science 196:307-308
218. Solomon GF 1969 Stress and antibody response in rats. Int Arch
Allergy 35:97-104
219. Kiecolt-Glazer JK, Glazer R 1991 Stress and immune functions in
humans. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 849-867
220. Keller SE, Schleifer S, Demetrikopoulos MK 1991 Stress-induced
changes in immune functions in animals: hypothalamus-pituitaryadrenal influences. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 771787
221. Bohus B, Koolhaas JM 1991 Psychoimmunology of social factors
in rodents and other subprimate vertebrates. In: Ader R, Felten D,
Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc,
New York, pp 807-830
222. Fernandes G, Halberg F, Yunis EJ, Good RA1976 Circadian rhythmic plaque-forming cell response spleen from mice immunized
with SRBC. J Immunol 117:962-966
223. Ader R, Cohen N1982 Behaviorally conditioned immunosuppression and murine systemic lupus erythematosus. Science 215:1534—
1536
224. Ader R, Grota LJ, Cohen N 1987 Conditioning phenomena and
immune functions. Ann NY Acad Sci 496:532-544
Vol. 17, No. 1
225. Gorczynski RM, Macrae S, Kennedy M1982 Conditioned immune
response associated with allogeneic skin grafts in mice. J Immunol
129:704-709
226. Gorczynski RM, Kennedy M, Ciampi A 1985 Cimetidine reverses
tumor growth enhancement of plasmacytoma tumors in mice demonstrating conditioned immunosuppression. J Immunol 134:42614266
227. Klosterhalfen W, Klosterhalfen S 1983 Pavlovian conditioning of
immunosuppression modifies adjuvant arthritis in rats. Behav
Neurosci 97:663-666
228. Kester MV, Phillips TL, Gracy RW 1977 Changes in glycolytic
enzyme levels and isozyme expression in human lymphocytes
during blast transformation Arch Biochem Biophys 183:700-709
229. Roszman TL, Carlson SL 1991 Neurotransmitters and molecular
signaling in the immune response In: Ader R, Felten D, Cohen N
(eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New
York, pp 311-335
230. Farrar WL, Ferris DK, Harel-Bellan A 1990 Lymphokine-induced
molecular transduction. In: Oppenheim JJ, Shevach EM (eds) Immunophysiology: The Role of Cells and Cytokines in Immunity and
Inflammation. Oxford University Press, Inc, New York, pp 67-87
231. Hadden JW 1983 Cyclic nucleotides and related mechanism in
immune regulation: a mini review. In: Fabris N, Garaci W, Hadden
J, Mitchison NA (eds) Immunoregulation. Plenum Press, New
York, pp 201-230
232. Hadden JW, Hadden EM, Coffey RG 1991 First and second messengers in the development and function of thymus-dependent
lymphocytes. In: Ader R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 529-560
233. Besedovsky HO, del Rey A, Sorkin E 1979 Role of prethymic cells
in acquisition of self-tolerance. J Exp Med 150:1351-1358
234. Speiser DE, Stiibi U, Zinkemagel RM 1992 Extrathymic positive
selection of alpha beta T-cell precursors in nude mice. Nature
355:170-172
235. Vacchio MS, Papadopoulos V, Ashwell JD 1994 Steroid production in the thymus: implications for thymocyte selection. J Exp Med
179:1835-1846
236. Besedovsky HO 1971 Delay in skin allograft rejection in rats
grafted with fetal adrenal glands. Experientia 27:697-698
237. Geenen V, Robert F, Defresne M-P, Boniver J, Legros J-J,
Franchimont P1989 Neuroendocrinology of the thymus. Horm Res
31:81-84
238. Dardenne M, Savino W 1994 Control of thymus physiology by
peptidic hormones and neuropeptides. Immunol Today 15:518523
239. Ernstrom U, Sandberg G 1973 Effects of alpha- and beta-receptor
stimulation on the release of lymphocytes and granulocytes from
the spleen. Scand J Haematol 11:275-286
240. Ernstrom U, Soder O 1975 Influence of adrenaline on the dissemination of antibody-producing cells from the spleen. Clin Exp Immunol 21:131-140
241. Ottaway CA 1984 In vivo alteration of receptors for vasoactive
intestinal peptide changes the in vivo localization of mouse T cells.
J Exp Med 160:1054-1069
242. Ottaway CA 1985 Evidence for local neuromodulation of T cell
migration in vivo. Adv Exp Med Biol 186:637-645
243. Moore TC 1984 Modification of lymphocyte traffic by vasoactive
neurotransmitter substances. Immunology 52:511-518
244. Ruff M, Schiffmann E, Terranova V, Pert CB 1985 Neuropeptides
are chemoattractants for human tumor cells and monocytes. A
possible mechanism for metastasis. Clin Immunol Immunopathol
37:387-396
245. Ruff MR, Wahl SM, Mergenhagen S, Pert CB 1985 Opiate receptor
mediated chemotaxis of human monocytes. Neuropeptides 5:363366
246. Sacerdote P, Ruff M, Pert C 1988 VIP , 12 is a ligand for the
CD4/human immunodeficiency virus receptor. Ann NY Acad Sci
527:574-578
247. De La Fuente M, Delgado M, Del Rio M, Garrido E, Leceta J,
Hernanz A, Gomariz RP 1994 Vasoactive intestinal peptide modulation of adherence and mobility in rat peritoneal lymphocytes
and macrophages. Peptides 15:1157-1163
248. Scicchittano R, Dazin P, Bienenstock J, Payan D, Stanisz AM 1987
February, 1996
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
264.
265.
266.
267.
268.
269.
270.
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
Distribution of somatostatin receptors on murine spleen and Peyer's patch T and B lymphocytes. Brain Behav Immun 1:173-184
Stead RH, Tomioka M, Quinonez G, Simon GT, Felten SY,
Bienenstock J 1987 Intestinal mucosal mast cells in normal and
nematode-infected rat intestines are in intimate contact with peptidergic nerves. Proc Natl Acad Sci USA 84:2975-2979
Wahl SM, Altman LC, Rosenstreich DL 1975 Inhibition of in vitro
lymphokine synthesis by glucocorticoids. J Immunol 115:476-481
Gillis S, Crabtree GR, Smith K 1979 Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogeninduced lymphocyte proliferation. J Immunol 123:1624-1631
Gillis S, Crabtree GR, Smith K 1979 Glucocorticoid-induced inhibition of T cell growth factor production. II. The effect on the in
vitro generation of cytolytic T cells. J Immunol 123:1632-1638
Kelso A, Munck A 1984 Glucocorticoid inhibition of lymphokine
secretion by alloreactive T lymphocyte clones. J Immunol 133:784791
Snyder DS, Unanue ER 1982 Corticosteroids inhibit murine macrophage la expression and interleukin-1 production. J Immunol
129:1803-1805
Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A 1986
Control of cachectin (tumor necrosis factor) synthesis: mechanisms
of endotoxin resistance. Science 232:977-980
Daynes RA, Araneo BA1989 Contrasting effects of glucocorticoids
on the capacity of T cells to produce the growth factors interleukin
2 and interleukin 4. Eur J Immunol 19:2319-2325
Akahoshi T, Oppenheim JJ, Matsushima KJ 1988 Induction of
high-affinity interleukin 1 receptors on human peripheral blood
lymphocytes by glucocorticoid hormones. J Exp Med 167:924-936
Redondo JM, Fresno M, Lopez-Rivas A 1988 Inhibition of interleukin 2-induced proliferation of cloned murine T cells by glucocorticoids. Possible involvement of an inhibitory protein. Eur J
Immunol 18:1555-1559
Bauer J, Lengyel G, Bauer TM, Acs G, Gerok W 1989 Regulation
of interleukin-6 receptor expression in human monocytes and
hepatocytes. FEBS Lett 249:27-30
Bermudez LE, Wu M, Young LS 1990 Effect of stress-related hormones on macrophage receptors and response to rumor necrosis
factor. Lymphokine Res 9:137-145
Mukherjee P, Mastro AM, Hymer WC 1990 Prolactin induction of
interleukin-2 receptors on rat splenic lymphocytes. Endocrinology
126:88-94
Koff WC, Fann AV, Dunegan MA, Lachman LB 1986 Catecholamine-induced suppression of interleukin-1 production. Lymphokine Res 5:239-247
Spengler RN, Allen RM, Remick DG, Strieter RM, Kunkel SL
1990 Stimulation of alpha-adrenergic receptor augments the production of macrophage-derived tumor necrosis factor. J Immunol
145:1430-1434
Lotz M, Vaughan JH, Carson DA 1988 Effect of neuropeptides on
the production of inflammatory cytokines by human monocytes.
Science 241:1218-1221
Muscettola M, Grasso G 1990 Somatostatin and vasoactive intestinal peptide reduce interferon gamma production by human peripheral blood mononuclear cells. Immunobiology 180:419-430
Hart R, Dancygier H, Wagner F, Niedermeyer H, Classen M 1988
Substance P modulates lymphokine activities in supernatants of
cultured human duodenal biopsies. Immunol Lett 19:133-136
Feldman RD, Hunninghake GW, McArdle WL 1987 Beta-adrenergic-receptor-mediated suppression of interleukin 2 receptors in
human lymphocytes. J Immunol 139:3355-3359
Rhodes J, Ivanyi J, Cozens P1986 Antigen presentation by human
monocytes: effects of modifying major histocompatibility complex
class II antigen expression and interleukin 1 production by using
recombinant interferons and corticosteroids. Eur J Immunol 16:
370-375
Shen L, Guyre P, Ball E, Fanger M 1986 Glucocorticoid enhances
gamma interferon effects on human monocyte antigen expression
and ADCC. Clin Exp Immunol 65:387-395
Frohman E, Vayuvegula B, Gupta S, van den Noort S 1988 Norepinephrine inhibits gamma-interferon-induced major histocompatibility class II (la) antigen expression on cultured astrocytes via
271.
272.
273.
274.
275.
276.
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
95
beta-2-adrenergic signal transduction mechanisms. Proc Natl Acad
Sci USA 85:1292-1296
Frohman E, Frohman T, Vayuvegula B, Gupta S, van den Noort
S 1988 Vasoactive intestinal polypeptide inhibits the expression of
the MHC class II antigens on astrocytes. J Neurol Sci 88:339-346
Fauci AS, Dale DC 1974 The effects of in vivo hydrocortisone on
subpopulations of human lymphocytes. J Clin Invest 53:240-246
Fauci AS 1976 Mechanism of corticosteroid action on lymphocyte
subpopulations. II. Differential effects of in vivo hydrocortisone,
prednisone and dexamethasone on in vitro expression of lymphocyte function. Clin Exp Immunol 24:54-62
Elliott EV, Sinclair NRStC 1968 Effect of cortisone acetate on 19S
and 7S haemolysin antibody. Immunology 15:643-652
Streng CB, Nathan P 1973 The immune response in steroid deficient mice. Immunology 24:559-565
Adelman DC, Goetzl EJ, Hassner A 1991 Unique suppression of
human blood mononuclear leukocyte (ML) production of IgG by
prolonged exposure to vasoactive intestinal peptide (VIP). J Allergy
Clin Immunol 87:260 (Abstract)
Besedovsky HO, del Rey A, Sorkin E1981 Lymphokine containing
supernatants from Con A-stimulated cells increase corticosterone
blood levels. J Immunol 126:385-387
Besedovsky HO, del Rey A, Sorkin E, Lotz W, Schwulera U 1985
Lymphoid cells produce an immunoregulatory glucocorticoid increasing factor (GIF) acting through the pituitary gland. Clin Exp
Immunol 59:622-628
Besedovsky HO, del Rey A, Sorkin E, Da Prada M, Burri R,
Honegger CG 1983 The immune response evokes changes in brain
noradrenergic neurons. Science 221:564-566
Besedovsky HO, Sorkin E, Mueller J 1975 Hormonal changes
during the immune response. Proc Soc Exp Biol 150:466-479
Besedovsky HO, Sorkin E 1977 Network of immune-neuroendocrine interactions. Clin Exp Immunol 27:1-12
Besedovsky H, del Rey A, Sorkin E, Dinarello CA 1986 Immunoregulatory feedback between interleukin-1 and glucocorticoid
hormones. Science 233:652-654
Berkenbosch F, de Goeij DEC, del Rey A, Besedovsky H 1989
Neuroendocrine, sympathetic and metabolic responses induced by
interleukin-1. Neuroendocrinology 50:570-576
Naitoh Y, Fukata J, Tominaga T, Nakai Y, Tamai S, Mori K, Imura
H1988 Interleukin-6 stimulates the secretion of adrenocorticotropic
hormone in conscious, freely-moving rats. Biochem Biophys Res
Commun 155:1459-1463
Sharp BM, Matta SG, Peterson PK, Newton R, Chao C, Mcallen
K 1989 Tumor necrosis factor-alpha is a potent ACTH secretagogue: comparison to interleukin-1 beta. Endocrinology 124:3131—
3133
Holsboer F, Stalla GK, von Bardeleben U, Hammann K, Muller
H, Muller OA 1988 Acute adrenocortical stimulation by recombinant gamma interferon in human controls. Life Sci 42:1-5
Vahouny GV, Kyeyune-Nyombi E, McGillis JP, Tare NS, Huang
KY, Tomes R Goldstein AL, Hall NR1983 Thymosin peptides and
lymphomonokines do not directly stimulate adrenal corticosteroid
production in vitro. J Immunol 130:791-794
Besedovsky HO, del Rey A, Klusman I, Furukawa H, Monge
Arditi G, Kabiersch A 1991 Cytokines as modulators of the hypothalamus-pituitary-adrenal axis. J Steroid Biochem Mol Biol 40:
613-618
Besedovsky HO, del Rey A 1989 Mechanism of virus-induced
stimulation of the hypothalamus-pituitary-adrenal axis. J Steroid
Biochem 34:235-239
Rivier C, Chizzonite R, Vale W 1989 In the mouse, the activation
of the hypothalamic-pituitary-adrenal axis by a lipopolysaccharide
(endotoxin) is mediated through interleukin-1. Endocrinology 125:
2800-2805
Perlstein RS, Mougey EH, Jackson WE, Neta R 1991 Interleukin-1
and interleukin-6 act synergistically to stimulate the release of
adrenocorticotropic hormone in vivo. Lymphokine Cytokine Res
10:141-146
Frederic F, Oliver C, Wollman E, Delhaye Bouchaud N, Mariani
J 1993 IL-1 and LPS induce a sexually dimorphic response of the
hypothalamo-pituitary-adrenal axis in several mouse strains. Eur
Cytokine Netw 4:321-329
96
BESEDOVSKY AND DEL REY
293. Besedovsky H, del Rey A 1987 Neuroendocrine and metabolic
responses induced by interleukin-1. J Neurosci Res 18:172-178
294. Rivier C 1994 Stimulatory effect of interleukin-1 beta on the hypothalamic-pituitary-adrenal axis of the rat: influence of age, gender and circulating sex steroids. J Endocrinol 140:365-372
295. Berkenbosch F, van Oers J, del Rey A, Tilders F, Besedovsky H
1987 Corticotropin-releasing factor-producing neurons in the rat
activated by interleukin-1. Science 238:524-526
296. Sapolsky R, Rivier C, Yamamoto G, Plotsky P, Vale W 1987
Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science 238:522-524
297. Uehara A, Gottschall PE, Dahl RR, Arimura A 1987 Interleukin-1
stimulates ACTH release by an indirect action which requires endogenous corticotropin releasing factor. Endocrinology 121:15801582
298. Uehara A, Gottschall PE, Dahl RR, Arimura A 1987 Stimulation
of ACTH release by human interleukin-1 beta, but not by interleukin-1 alpha, in conscious, freely-moving rats. Biochem Biophys
Res Commun 146:1286-1290
299. Suda T, Tozawa F, Ushiyama T, Sumitomo T, Yamada M, Demura
H 1990 Interleukin-1 stimulates corticotropin-releasing factor gene
expression in rat hypothalamus. Endocrinology 126:1223-1228
300. Harbuz MS, Stephanou A, Sarlis N, Lightman SL 1992 The effects
of recombinant human interleukin (IL)-l alpha, IL-1 beta or IL-6 on
hypothalamo-pituitary-adrenal axis activation. J Endocrinol 133:
349-355
301. Nakamura H, Motoyoshi S, Kadokawa T1988 Anti-inflammatory
action of interleukin 1 through the pituitary-adrenal axis in rats.
Eur J Pharmacol 151:67-73
302. Gwosdow AR, Kumar MS, Bode HH 1990 Interleukin 1 stimulation of the hypothalamic-pituitary-adrenal axis. Am J Physiol 258:
E65-E70
303. Matta SG, Weatherbee J, Sharp BM 1992 A central mechanism is
involved in the secretion of ACTH in response to IL-6 in rats:
comparison to and interaction with IL-1 beta. Neuroendocrinology
56:516-525
304. Bataillard A, del Rey A, Klusman I, Arditi GM, Besedovsky HO
1992 Interleukin-1 stimulates aldosterone secretion: involvement of
renin, ACTH, and prostaglandins. Am J Physiol 263:R840-R844
305. Watanabe T, Morimoto A, Tan N, Makisumi T, Shimada SG,
Nakamori T, Murakami N 1994 ACTH response induced in capsaicin-desensitized rats by intravenous injection of interleukin-1 or
prostaglandin E. J Physiol (Lond) 475:139-145
306. Rivier C, Shen GH 1994 In the rat, endogenous nitric oxide modulates the response of the hypothalamic-pituitary-adrenal axis to
interleukin-1 beta, vasopressin, and oxytocin. J Neurosci 14:19851993
307. Weidenfeld J, Abramsky O, Ovadia H 1989 Evidence for the
involvement of the central adrenergic system in interleukin 1-induced adrenocortical response. Neuropharmacology 28:1411-1414
308. Brown R, Li Z, Vriend CY, Nirula R, Janz L, Falk J, Nance DM,
Dyck DG, Greenberg AH 1991 Suppression of splenic macrophage
interleukin-1 secretion following intracerebroventricular injection
of interleukin-1 beta: evidence for pituitary-adrenal and sympathetic control. Cell Immunol 132:84-93
309. Ovadia H, Abramsky O, Barak V, Conforti N, Saphier D,
Weidenfeld J1989 Effect of interleukin-1 on adrenocortical activity
in intact and hypothalamic deafferentated male rats. Exp Brain Res
76:246-249
310. Naito Y, Fukata J, Nakaishi S, Nakai Y, Hirai Y, Tamai S, Mori
K, Imura H1990 Chronic effects of interleukin-1 on hypothalamus,
pituitary and adrenal glands in rat. Neuroendocrinology 516:637641
311. Weiss JM, Sundar SK, Cierpial MA, Ritchie JC 1991 Effects of
interleukin-1 infused into brain are antagonized by alpha-MSH in
a dose-dependent manner. Eur J Pharmacol 192:177-179
312. Takahashi H, Nishimura M, Sakamoto M, Ikegaki I, Nakanishi
T, Yoshimura M 1992 Effects of interleukin-1 beta on blood pressure, sympathetic nerve activity, and pituitary endocrine functions
in anesthetized rats. Am J Hypertens 5:224-229
313. Sweep CG, van der Meer MJ, Hermus AR, Smals AG, van der
Meer JW, Pesman GJ, Willemsen SJ, Benraad TJ, Kloppenborg
PW 1992 Chronic stimulation of the pituitary-adrenal axis in rats
314.
315.
316.
317.
318.
319.
320.
321.
322.
323.
324.
325.
326.
327.
328.
329.
330.
331.
332.
Vol. 17, No. 1
by interleukin-1 beta infusion: in vivo and in vitro studies. Endocrinology 130:1153-1164
O'Grady MP, Hall NR, Menzies RA 1993 Interleukin-1 beta stimulates adrenocorticotropin and corticosterone release in 10-day-old
rat pups. Psychoneuroendocrinology 18:241-247
Hashimoto K, Hirasawa R, Makino S 1993 Comparison of the
effects of intra-third ventricular administration of interleukin-1 or
platelet activating factor on ACTH secretion and the sympatheticadrenomedullary system in conscious rats. Acta Med Okayama
47:1-6
Linthorst AC, Flachskamm C, Holsboer F, Reul JM 1994 Local
administration of recombinant human interleukin-1 beta in the rat
hippocampus increases serotonergic neurotransmission, hypothalamic-pituitary-adrenocortical axis activity, and body temperature.
Endocrinology 135:520-532
Rivest S, Rivier C 1994 Stress and interleukin-1 beta-induced activation of c-fos, NGFI-B and CRF gene expression in the hypothalamic PVN: comparison between Sprague-Dawley, Fisher-344
and Lewis rats. J Neuroendocrinol 6:101-117
Levine S, Berkenbosch F, Suchecki D, Tilders FJ 1994 Pituitaryadrenal and interleukin-6 responses to recombinant interleukin-1
in neonatal rats. Psychoneuroendocrinology 19:143-153
Rettori V, Jurcovicova J, McCann SM 1987 Central action of interleukin-1 in altering the release of TSH, growth hormone, and
prolactin in the male rat. J Neurosci Res 18:179-183
Rivier C, Vale W1989 In the rat, interleukin-1 alpha acts at the level
of the brain and the gonads to interfere with gonadotropin and sex
steroid secretion. Endocrinology 124:2105-2109
Rivest S, Rivier C 1995 The role of corticotropin-releasing factor
and interleukin-1 in the regulation of neurons controlling reproductive functions. Endocr Rev 16:177-199
Bonavera JJ, Kalra SP, Kalra PS 1993 Mode of action of interleukin-1 in suppression of pituitary LH release in castrated male rats.
Brain Res 612:1-8
Hermus RM, Sweep CG, van der Meer MJ, Ross HA, Smals AG,
Benraad TJ, Kloppenborg PW 1992 Continuous infusion of interleukin-1 beta induces a nonthyroidal illness syndrome in the rat.
Endocrinology 131:2139-2146
Rivest S, Rivier C 1993 Interleukin-1 beta inhibits the endogenous
expression of the early gene c-fos located within the nucleus of
LH-RH neurons and interferes with hypothalamic LH-RH release
during proestrus in the rat. Brain Res 613:132-142
Rivest S, Lee S, Attardi B, Rivier C 1993 The chronic intracerebroventricular infusion of interleukin-1 beta alters the activity of
the hypothalamic-pituitary-gonadal axis of cycling rats. I. Effect on
LHRH and gonadotropin biosynthesis and secretion. Endocrinology 133:2424-2430
Shalts E, Feng YJ, Ferin M, Wardlaw SL 1992 Alpha-melanocytestimulating hormone antagonizes the neuroendocrine effects of
corticotropin-releasing factor and interleukin-1 alpha in the primate. Endocrinology 131:132-138
Feng YJ, Shalts E, Xia LN, Rivier J, Rivier C, Vale W, Ferin M1991
An inhibitory effects of interleukin-1 a on basal gonadotropin release in the ovariectomized rhesus monkey: reversal by a corticotropin-releasing factor antagonist. Endocrinology 128:2077-2082
Rotiroti D, Ciriaco E, Germana GP, Naccari F, Gratteri S, Laura
R, Abbate F, Germana G 1993 Stimulatory effects on lactotrophs
and crop-sac of interleukin-1 and interleukin-2 in pigeons (Columba
livia). Funct Neurol 8:205-210
Harbuz MS, Stephanou A, Knight RA, Chover Gonzalez AJ,
Lightman SL 1992 Action of interleukin-2 and interleukin-4 on CRF
mRNA in the hypothalamus and POMC mRNA in the anterior
pituitary. Brain Behav Immun 6:214-222
Lyson K, McCann SM 1992 Induction of adrenocorticotropic hormone release by interleukin-6 in vivo and in vitro. Ann NY Acad Sci
650:182-185
Lyson K, McCann SM 1991 The effect of interleukin-6 on pituitary
hormone release in vivo and in vitro. Neuroendocrinology 54:262266
Bernardini R, Kamilaris TC, Calogero AE, Johnson EO, Gomez
MT, Gold PW, Chrousos GP 1990 Interactions between rumor
necrosis factor-alpha, hypothalamic corticotropin-releasing hor-
February, 1996
333.
334.
335.
336.
337.
338.
339.
340.
341.
342.
343.
344.
345.
346.
347.
348.
349.
350.
351.
352.
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
mone, and adrenocorticotropin secretion in the rat. Endocrinology
126:2876-2881
Sharp BM, Matta SG 1993 Prostaglandins mediate the adrenocorticotropin response to tumor necrosis factor in rats. Endocrinology
132:269-274
Pang XP, Hershman JM, Mirell CJ, Pekary AE 1989 Impairment
of hypothalamic-pituitary-thyroid function in rats treated with human recombinant tumor necrosis factor-alpha (cachectin). Endocrinology 125:76-84
Rettori V, Milenkovic L, Beutler BA, McCann SM 1989 Hypothalamic action of cachectin to alter pituitary hormone release.
Brain Res Bull 23:471-475
Van der Poll T, Romijn JA, Endert E, Sauerwein HP 1993 Effects
of tumor necrosis factor on the hypothalamic-pituitary-testicular
axis in healthy men. Metabolism 42:303-307
Woloski BM, Smith EM, Meyer III WJ, Fuller GM, Blalock JE1985
Corticotropin-releasing activity of monokines. Science 230:10351037
Bernton EW, Beach JE, Holaday JW, Smallridge RC, Fein HG 1987
Release of multiple hormones by a direct action of interleukin-1 on
pituitary cells. Science 238:519-521
Uehara A, Gillis S, Arimura A 1987 Effects of interleukin-1 on
hormone release from normal rat pituitary cells in primary culture.
Neuroendocrinology 45:343-347
Kehrer P, Turnill D, Dayer JM, Muller AF, Gaillard RC 1988
Human recombinant interleukin-1 beta and -alpha, but not recombinant tumor necrosis factor alpha stimulate ACTH release from rat
anterior pituitary cells in vitro in a prostaglandin E2 and cAMP
independent manner. Neuroendocrinology 48:160-166
Suda T, Tozawa F, Ushiyama T, Tomori N, Sumitomo T,
Nakagami Y, Yamada M, Demura H, Shizume K 1989 Effects of
protein kinase-C-related adrenocorticotropin secretagogues and
interleukin-1 on proopiomelanocortin gene expression in rat anterior pituitary cells. Endocrinology 124:1444-1449
Boyle M, Yamamoto G, Chen M, Rivier J, Vale W1988 Interleukin
1 prevents loss of corticotropic responsiveness to beta-adrenergic
stimulation in vitro. Proc Natl Acad Sci USA 85:5556-5560
Beach JE, Smallridge RC, Kinzer CA, Bernton EW, Holaday JW,
Fein HG 1989 Rapid release of multiple hormones from rat pituitaries perifused with recombinant interleukin-1. Life Sci 44:1—7
Schettini G, Landolfi E, Grimaldi M, Meucci O, Postiglione A,
Florio T, Ventra C 1989 Interleukin 1 beta inhibition of TRHstimulated prolactin secretion and phosphoinositides metabolism.
Biochem Biophys Res Commun 165:496-505
Schettini G, Florio T, Meucci O, Landolfi E, Grimaldi M,
Lombardi G, Scala G, Leong D1990 Interleukin-1-beta modulation
of prolactin secretion from rat anterior pituitary cells: involvement
of adenylate cyclase activity and calcium mobilization. Endocrinology 126:1435-1441
Christensen JD, Hansen EW, Fjalland B 1989 Interleukin-1 beta
stimulates the release of vasopressin from rat neurohypophysis.
Eur J Pharmacol 171:233-235
Christensen JD, Hansen EW, Fjalland B 1990 Influence of interleukin-1 beta on the secretion of oxytocin and vasopressin from the
isolated rat neurohypophysis. Pharmacol Toxicol 67:81-83
Yamaguchi M, Koike K, Yoshimoto Y, Ikegami H, Miyake A,
Tanizawa O 1991 Effect of TNF-alpha on prolactin secretion from
rat anterior pituitary and dopamine release from the hypothalamus: comparison with the effect of interleukin-1 beta. Endocrinol
Jpn 38:357-361
Murata T, Ying SY 1991 Effects of interleukin-1 beta on secretion
of follicle-stimulating hormone (FSH) and luteinizing hormone
(LH) by cultured rat anterior pituitary cells. Life Sci 49:447-453
Parsadaniantz SM, Lenoir V, Terlain B, Kerdelhue B 1993 Lack of
effect of interleukins 1 alpha and 1 beta, during in vitro perifusion,
on anterior pituitary release of adrenocorticotropic hormone and
beta endorphin in the male rat. J Neurosci Res 34:315-323
Navarra P, Tsagarakis S, Faria MS, Rees LH, Besser GM,
Grossman AB 1991 Interleukins-1 and -6 stimulate the release of
corticotropin-releasing hormone-41 from rat hypothalamus in vitro
via the eicosanoid cyclooxygenase pathway. Endocrinology 128:
37-44
Spangelo BL, Judd AM, Isakson PC, MacLeod RM 1989 Inter-
353.
354.
355.
356.
357.
358.
359.
360.
361.
362.
363.
364.
365.
366.
367.
368.
369.
370.
371.
372.
97
leukin-6 stimulates anterior pituitary hormone release in vitro.
Endocrinology 125:575-577
Yamaguchi M, Sakata M, Matsuzaki N, Koike K, Miyake A,
Tanizawa 01990 Induction by tumor necrosis factor-alpha of rapid
release of immunoreactive and bioactive luteinizing hormone from
rat pituitary cells in vitro. Neuroendocrinology 52:468-472
Walton PE, Cronin MJ 1989 Tumor necrosis factor-alpha inhibits
growth hormone secretion from cultured anterior pituitary cells.
Endocrinology 125:925-929
Gaillard RC, Turnill D, Sappino P, Muller AF 1990 Tumor necrosis factor alpha inhibits the hormonal response of the pituitary
gland to hypothalamic releasing factors. Endocrinology 127:101106
Koike K, Hirota K, Ohmichi M, Kadowaki K, Ikegami H,
Yamaguchi M, Miyake A, Tanizawa 01991 Tumor necrosis factoralpha increases release of arachidonate and prolactin from rat anterior pituitary cells. Endocrinology 128:2791-2798
Pang XP, Yoshimura M, Hershman JM 1993 Suppression of rat
thyrotroph and thyroid cell function by tumor necrosis factoralpha. Thyroid 3:325-330
Walton PE, Cronin MJ 1990 Tumor necrosis factor-alpha and interferon-gamma reduce prolactin release in vitro. Am J Physiol
259:E672-E676
Vankelecom H, Carmeliet P, Heremans H, Van Damme J,
Dijkmans R, Billiau A, Denef C 1990 Interferon-gamma inhibits
stimulated adrenocorticotropin, prolactin, and growth hormone
secretion in normal rat anterior pituitary cell cultures. Endocrinology 126:2919-2926
Gwosdow AR, O'Connell NA, Spencer JA, Kumar MS, Agarwal
RK, Bode HH, Abou Samra AB 1992 Interleukin-1-induced corticosterone release occurs by an adrenergic mechanism from rat
adrenal gland. Am J Physiol 263:E461-E466
Harlin CA, Parker Jr CR 1991 Investigation of the effect of interleukin-1 beta on steroidogenesis in the human fetal adrenal gland.
Steroids 56:72-76
Roh MS, Drazenovich KA, Barbose JJ, Dinarello CA, Cobb CF
1987 Direct stimulation of the adrenal cortex by interleukin-1.
Surgery 102:140-146
Whitcomb RW, Linehan WM, Wahl LM, Knazek RA 1988 Monocytes stimulate cortisol production by cultured human adrenocortical cells. J Clin Endocrinol Metab 66:33-38
Andreis PG, Neri G, Belloni AS, Mazzocchi G, Kasprzak A,
Nussdorfer GG 1991 Interleukin-1 beta enhances corticosterone
secretion by acting directly on the rat adrenal gland. Endocrinology
129:53-57
Tominaga T, Fukata J, Naito Y, Usui T, Murakami N, Fukushima
M, Nakai Y, Hirai Y, Imura H 1991 Prostaglandin-dependent in
vitro stimulation of adrenocortical steroidogenesis by interleukins.
Endocrinology 128:526-531
Andreis PG, Neri G, Meneghelli V, Mazzocchi G, Nussdorfer GG
1992 Effects of interleukin-1 beta on the renin-angiotensin-aldosterone system in rats. Res Exp Med (Berl) 192:1-6
Eskay RL, Eiden LE 1992 Interleukin-1 alpha and tumor necrosis
factor-alpha differentially regulate enkephalin, vasoactive intestinal polypeptide, neurotensin, and substance P biosynthesis in chromaffin cells. Endocrinology 130:2252-2258
O'Connell NA, Kumar A, Chatzipanteli K, Mohan A, Agarwal
RK, Head C, Bornstein SR, Abou Samra AB, Gwosdow AR 1994
Interleukin-1 regulates corticosterone secretion from the rat adrenal gland through a catecholamine-dependent and prostaglandin
E2-independent mechanism. Endocrinology 135:460-467
Natarajan R, Ploszaj S, Horton R, Nadler J 1989 Tumor necrosis
factor and interleukin-1 are potent inhibitors of angiotensin-IIinduced aldosterone synthesis. Endocrinology 125:3084-3089
Salas MA, Evans SW, Levell MJ, Whicher JT 1990 Interleukin-6
and ACTH act synergistically to stimulate the release of corticosterone from adrenal gland cells. Clin Exp Immunol 79:470-473
Ilvesmaki V, Jaattela M, Saksela E, Voutilainen R 1993 Tumor
necrosis factor-alpha and interferon-gamma inhibit insulin-like
growth factor II gene expression in human fetal adrenal cell cultures. Mol Cell Endocrinol 91:59-65
Dubuis JM, Dayer JM, Siegrist Kaiser CA, Burger AG 1988 Human recombinant interleukin-1 beta decreases plasma thyroid hor-
98
373.
374.
375.
376.
377.
378.
379.
380.
381.
382.
383.
384.
385.
386.
387.
388.
389.
390.
BESEDOVSKY AND DEL REY
mone and thyroid stimulating hormone levels in rats. Endocrinology 123:2175-2181
Kakucska I, Romero LI, Clark BD, Rondeel JM, Qi Y, Alex S,
Emerson CH, Lechan RM 1994 Suppression of thyrotropin-releasing hormone gene expression by interleukin-1-beta in the rat: implications for nonthyroidal illness. Neuroendocrinology 59:129137
Fujii T, Sato K, Ozawa M, Kasono K, Imamura H, Kanaji Y,
Tsushima T, Shizume K 1989 Effect of interleukin-1 (IL-1) on
thyroid hormone metabolism in mice: stimulation by IL-1 of iodothyronine 5'-deiodinating activity (type I) in the liver. Endocrinology 124:167-174
Enomoto T, Sugawa H, Kosugi S, Inoue D, Mori T, Imura H 1990
Prolonged effects of recombinant human interleukin-1 alpha on
mouse thyroid function. Endocrinology 127:2322-2327
Sweep CG, van der Meer MJ, Ross HA, Vranckx R, Visser TJ,
Hermus AR 1992 Chronic infusion of TNF-alpha reduces plasma
T4 binding without affecting pituitary-thyroid activity in rats. Am
J Physiol 263:E1099-E1105
Ozawa M, Sato K, Han DC, Kawakami M, Tsushima T, Shizume
K 1988 Effects of tumor necrosis factor-alpha/cachectin on thyroid
hormone metabolism in mice. Endocrinology 123:1461-1467
Van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP 1990
Tumor necrosis factor: a putative mediator of the sick euthyroid
syndrome in man. J Clin Endocrinol Metab 71:1567-1572
Rasmussen AK, Kayser L, Bech K, Feldt Rasmussen U, Perrild H,
Bendtzen K 1990 Differential effects of interleukin 1 alpha and 1
beta on cultured human and rat thyroid epithelial cells. Acta
Endocrinol (Copenh) 122:520-526
Kung AW, Lau KS 1990 Interleukin-1 beta modulates thyrotropininduced thyroglobulin mRNA transcription through 3',5'-cyclic
adenosine monophosphate. Endocrinology 127:1369-1374
Yamashita S, Kimura H, Ashizawa K, Nagayama Y, Hirayu H,
Izumi M, Nagataki S 1989 Interleukin-1 inhibits thyrotrophininduced human thyroglobulin gene expression. J Endocrinol 122:
177-183
Sato K, Satoh T, Shizume K, Ozawa M, Han DC, Imamura H,
Tsushima T, Demura H, Kanaji Y, Ito Y, Obara T, Fujimoto Y,
Kanaji Y1990 Inhibition of 125I organification and thyroid hormone
release by interleukin-1, tumor necrosis factor-alpha, and interferon-gamma in human thyrocytes in suspension culture. J Clin Endocrinol Metab 70:1735-1743
Krogh Rasmussen A, Kayser L, Bech K, Feldt Rasmussen U,
Perrild H, Bendtzen K 1991 Influence of interleukin 6 on the function of secondary cultures of human thyrocytes. Acta Endocrinol
(Copenh) 124:577-582
Tominaga T, Yamashita S, Nagayama Y, Morita S, Yokoyama N,
Izumi M, Nagataki S 1991 Interleukin 6 inhibits human thyroid
peroxidase gene expression. Acta Endocrinol (Copenh) 124:290294
Poth M, Tseng YC, Wartofsky L 1991 Inhibition of TSH activation
of human cultured thyroid cells by tumor necrosis factor: an explanation for decreased thyroid function in systemic illness? Thyroid 1:235-240
Nishikawa T, Yamashita S, Namba H, Usa T, Tominaga T,
Kimura H, Izumi M, Nagataki S1993 Interferon-gamma inhibition
of human thyrotropin receptor gene expression. J Clin Endocrinol
Metab 77:1084-1089
Spinas GA, Mandrup-Poulsen T, Molvig J, Baek L, Bendtzen K,
Dinarello CA, Nerup J 1986 Low concentrations of interleukin-1
stimulate and high concentrations inhibit insulin release from isolated rat islets of Langerhans. Acta Endocrinol (Copenh) 113:551558
Sandier S, Andersson A, Hellerstrom C 1987 Inhibitory effects of
interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets. Endocrinology
121:1424-1431
Wogensen LD, Mandrup Poulsen T, Markholst H, Molvig J,
Lernmark A, Hoist JJ, Dinarello CA, Nerup J 1988 Interleukin-1
potentiates glucose stimulated insulin release in the isolated perfused pancreas. Acta Endocrinol (Copenh) 117:302-306
Wogensen LD, Kolb Bachofen V, Christensen P, Dinarello CA,
Mandrup Poulsen T, Martin S, Nerup J 1990 Functional and mor-
391.
392.
393.
394.
395.
396.
397.
398.
399.
400.
401.
402.
403.
404.
405.
406.
407.
408.
409.
410.
411.
412.
Vol. 17, No. 1
phological effects of interleukin-1 beta on the perfused rat pancreas.
Diabetologia 33:15-23
Yelich MR 1990 In vivo endotoxin and IL-1 potentiate insulin
secretion in pancreatic islets. Am J Physiol 258:R1070-R1077
Yelich MR 1992 Effects of endotoxin and interleukin-1 on glucagon
and insulin secretion from the perfused rat pancreas. Pancreas
7:358-366
Rabinovitch A, Sumoski W, Rajotte RV, Warnock GL 1990 Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture. } Clin Endocrinol Metab 71:152-156
Vara E, Arias Diaz J, Garcia C, Balibrea JL 1994 Cytokine-induced
inhibition of lipid synthesis and hormone secretion by isolated
human islets. Pancreas 9:316-323
Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello
CA, Svenson M 1986 Cytotoxicity of human pi 7 interleukin-1 for
pancreatic islets of Langerhans. Science 232:1545-1547
Sjogren A, Holmes PV, Hillensjo T1991 Interleukin-1 alpha modulates luteinizing hormone stimulated cyclic AMP and progesterone release from human granulosa cells in vitro. Hum Reprod
6:910-913
Brannstrom M, Wang L, Norman RJ 1993 Ovulatory effect of
interleukin-1 beta on the perfused rat ovary. Endocrinology 132:
399-404
Roby KF, Terranova PF1990 Effects of tumor necrosis factor-alpha
in vitro on steroidogenesis of healthy and atretic follicles of the rat:
theca as a target. Endocrinology 126:2711-2718
Adashi EY, Resnick CE, Packman JN, Hurwitz A, Payne DW1990
Cytokine-mediated regulation of ovarian function: tumor necrosis
factor alpha inhibits gonadotropin-supported progesterone accumulation by differentiating and luteinized murine granulosa cells.
Am J Obstet Gynecol 162:889-896
Best CL, Pudney J, Anderson DJ, Hill JA 1994 Modulation of
human granulosa cell steroid production in vitro by tumor necrosis
factor alpha: implications of white blood cells in culture. Obstet
Gynecol 84:121-127
Fauser BC, Galway AB, Hsueh AJ 1989 Inhibitory actions of interleukin-1 beta on steroidogenesis in primary cultures of neonatal
rat testicular cells. Acta Endocrinol (Copenh) 120:401-408
Guo H, Calkins JH, Sigel MM, Lin T1990 Interleukin-2 is a potent
inhibitor of Leydig cell steroidogenesis. Endocrinology 127:12341239
Meikle AW, Cardoso de Sousa JC, Dacosta N, Bishop DK,
Samlowski WE 1992 Direct and indirect effects of murine interleukin-2, gamma interferon, and tumor necrosis factor on testosterone synthesis in mouse Leydig cells. J Androl 13:437-443
Warren DW, Pasupuleti V, Lu Y, Platler BW, Horton R 1990
Tumor necrosis factor and interleukin-1 stimulate testosterone secretion in adult male rat Leydig cells in vitro. J Androl 11:353-360
Mealy K, Robinson B, Millette CF, Majzoub J, Wilmore DW 1990
The testicular effects of tumor necrosis factor. Ann Surg 211:470475
Sun XR, Hedger MP, Risbridger GP 1993 The effect of testicular
macrophages and interleukin-1 on testosterone production by purified adult rat Leydig cells cultured under in vitro maintenance
conditions. Endocrinology 132:186-192
Watson ME, Newman RJ, Payne AM, Abdelrahim M, Francis GL
1994 The effect of macrophage conditioned media on Leydig cell
function. Ann Clin Lab Sci 24:84-95
Kavelaars A, Ballieux RE, Heijnen CJ 1989 The role of IL-1 in the
corticotropin-releasing factor and arginine-vasopressin-induced
secretion of immunoreactive beta-endorphin by human peripheral
blood mononuclear cells. J Immunol 142:2338-2342
Westly HJ, Kleiss AJ, Kelley KW, Wong PKY, Yuen PH 1986
Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene. J Exp Med 163:1589-1594
Hall NRS, O'Grady MP, Farah Jr JM 1991 Thymic hormones and
immune function: mediation via neuroendocrine circuits. In: Ader
R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2.
Academic Press Inc, New York, pp 515-528
Pouplard AGF, Bottazzo D, Doniach D, Roitt IV 1976 Binding of
human immunoglobulins to pituitary ACTH cells. Nature 261:142—
144
Cohen IRD, Elias R, Maron R, Shechter Y 1984 Immunization to
February, 1996
413.
414.
415.
416.
417.
418.
419.
420.
421.
422.
423.
424.
425.
426.
427.
428.
429.
430.
431.
432.
433.
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
insulin generates antiidiotypes that behave as antibodies to the
insulin hormones receptor and cause diabetes mellitus. In: Kohler
H, Urbain J, Cazenave PA (eds) Idiotypy in Biology and Medicine.
Academic Press, New York, pp 385-400
Strosberg AD 1984 Antiidiotypic antibodies as immunological internal images of hormones. In: Kohler H, Urbain J, Cazenave PA
(eds) Idiotypy in Biology and Medicine. Academic Press, New
York, pp 365-383
Aston R, Cowden WB, Ada GL1989 Antibody-mediated enhancement of hormone activity. Mol Immunol 26:435-446
Tsagarakis S, Gillies G, Rees LH, Besser M, Grossman A 1989
Interleukin-1 directly stimulates the release of corticotrophin releasing factor from rat hypothalamus. Neuroendocrinology 49:98101
Cambronero JC, Rivas FJ, Borrell J, Guaza C 1992 Release of
corticotropin-releasing factor from superfused rat hypothalami induced by interleukin-1 is not dependent on adrenergic mechanism.
Eur J Pharmacol 219:75-80
Kabiersch A, del Rey A, Honegger CG, Besedovsky HO 1988
Interleukin-1 induces changes in norepinephrine metabolism in the
rat brain. Brain Behav Immun 2:267-274
Masana MI, Heyes MP, Mefford IN 1991 Indomethacin prevents
increased catecholamine turnover in rat brain following systemic
endotoxin challenge. Prog Neuropsychopharmacol Biol Psychiatry
14:609-621
Mohankumar PS, Thyagarajan S, Quadri SK 1991 Interleukin-1
stimulates the release of dopamine and dihydroxyphenylacetic
acid from the hypothalamus in vivo. Life Sci 48:925-930
Gemma C, Ghezzi P, De Simoni MG 1991 Activation of the hypothalamic serotoninergic system by central interleukin-1. Eur J
Pharmacol 209:139-140
Shintani F, Kanba S, Nakaki T, Nibuya M, Kinoshita N, Suzuki
E, Yagi G, Kato R, Asai M1993 Interleukin-1 beta augments release
of norepinephrine, dopamine, and serotonin in the rat anterior
hypothalamus. J Neurosci 13:3574-3581
Dunn AJ 1988 Systemic interleukin-1 administration stimulates
hypothalamic norepinephrine metabolism parallelling the increased plasma corticosterone. Life Sci 43:429-435
Dunn AJ 1992 Endotoxin-induced activation of cerebral catecholamine, serotonin metabolism: comparison with interleukin-1. J
Pharmacol Exp Ther 261:964-969
Zalcman S, Green Johnson JM, Murray L, Nance DM, Dyck D,
Anisman H, Greenberg AH 1994 Cytokine-specific central monoamine alterations induced by interleukin-1, -2 and -6. Brain Res
643:40-49
Chang SL, Ren T, Zadina JE 1993 Interleukin-1 activation of FOS
proto-oncogene protein in the rat hypothalamus. Brain Res 617:
123-130
Ericsson A, Kovacs KJ, Sawchenko PE 1994 A functional anatomical analysis of central pathways subserving the effects of interleukin-1 on stress-related neuroendocrine neurons. J Neurosci 14:
897-913
Saphier D, Ovadia H 1990 Selective facilitation of putative corticotropin-releasing factor-secreting neurones by interleukin-1. Neurosci Lett 114:283-288
Kidron D, Saphier D, Ovadia H, Weidenfeld J, Abramsky O 1989
Central administration of immunomodulatory factors alters neural
activity and adrenocortical secretion. Brain Behav Immun 3:15-27
Wilkinson MF, Mathieson WB, Pittman QJ1993 Interleukin-1 beta
has excitatory effects on neurons of the bed nucleus of the stria
terminalis. Brain Res 625:342-346
Bartholomew SA, Hoffman SA1993 Effects of peripheral cytokine
injections on multiple unit activity in the anterior hypothalamic
area of the mouse. Brain Behav Immun 7:301-316
De Sarro GB, Ascioti C, Audino MG, Rispoli V, Nistico G 1989
In: Hadden JW, Masek K, Nistico G (eds) Interactions among CNS,
Neuroendocrine and Immune Systems. Pythagora Press, Rome, pp
351-364
Reyes Vazquez C, Prieto Gomez B, Georgiades JA, Dafny N 1984
Alpha and gamma interferons effects on cortical and hippocampal
neurons. Microiontophoretic application and single cell recording.
Int J Neurosci 25:113-121
Miller LG, Galpern WR, Dunlap K, Dinarello CA, Turner TJ1991
434.
435.
436.
437.
438.
439.
440.
441.
442.
443.
444.
445.
446.
447.
448.
449.
450.
451.
452.
453.
454.
455.
456.
457.
99
Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. Mol Pharmacol 39:105-108
Palazzolo DL, Quadri SK 1990 Interleukin-1 stimulates catecholamine release from the hypothalamus. Life Sci 47:2105-2109
Li Z, Inenage K, Kawano S, Kannan H, Yamashita H 1992 Interleukin-1 beta directly excites hypothalamic supraoptic neurons in
rats in vitro. Neuroreport 3:91-93
Zeise ML, Madamba S, Siggins GR 1992 Interleukin-1 beta increases synaptic inhibition in rat hippocampal pyramidal neurons
in vitro. Regul Pept 39:1-7
Li Z, Inenaga K, Yamashita H 1993 GABAergic inputs modulate
effects of interleukin-1 beta on supraoptic neurones in vitro. Neuroreport 5:181-183
Plata Salaman CR, Ffrench Mullen JM 1992 Interleukin-1 beta
depresses calcium currents in CA1 hippocampal neurons at pathophysiological concentrations. Brain Res Bull 29:221-223
Bellinger FP, Madamba S, Siggins GR 1993 Interleukin 1 beta
inhibits synaptic strength and long-term potentiation in the rat CA1
hippocampus. Brain Res 628:227-234
Konishi Y, Chui DH, Hirose H, Kunishita T, Tabira T 1993 Trophic effect of erythropoietin and other hematopoietic factors on
central cholinergic neurons in vitro and in vivo. Brain Res 609:29-35
Elenkov IJ, Kovacs K, Duda E, Stark E, Vizi ES 1992 Presynaptic
inhibitory effect of TNF-alpha on the release of noradrenaline in
isolated median eminence. J Neuroimmunol 41:117-120
Tancredi V, D'Arcangelo G, Grassi F, Tarroni P, Palmieri G,
Santoni A, Eusebi F 1992 Tumor necrosis factor alters synaptic
transmission in rat hippocampal slices. Neurosci Lett 146:176-178
Shibata M, Blatteis CM 1991 Human recombinant tumor necrosis
factor and interferon affect the activity of neurons in the organum
vasculosum laminae terminalis. Brain Res 562:323-326
Jonakait GM, Wei R, Sheng ZL, Hart RP, Ni L 1994 Interferongamma promotes cholinergic differentiation of embryonic septal
nuclei and adjacent basal forebrain. Neuron 12:1149-1159
D'Arcangelo G, Grassi F, Ragozzino D, Santoni A, Tancredi V,
Eusebi F 1991 Interferon inhibits synaptic potentiation in rat hippocampus. Brain Res 564:245-248
Muller M, Fontana A, Zbinden G, Gahwiler BH 1993 Effects of
interferons and hydrogen peroxide on CA3 pyramidal cells in rat
hippocampal slice cultures. Brain Res 619:157-162
Matta S, Singh J, Newton R, Sharp BM 1990 The adrenocorticotropin response to interleukin-1 beta instilled into the rat median
eminence depends on the local release of catecholamines. Endocrinology 127:2175-2182
Chuluyan HE, Saphier D, Rohn WM, Dunn AJ 1992 Noradrenergic innervation of the hypothalamus participates in adrenocortical responses to interleukin-1. Neuroendocrinology 56:106-111
Jonakait GM, Schotland S 1990 Conditioned medium from activated splenocytes increases substance P in sympathetic ganglia.
J Neurosci Res 26:24-30
Hart RP, Shadiack A, Jonakait GM 1991 Substance P gene expression is regulated by interleukin 1 in cultured sympathetic ganglia, J Neurosci Res 29:282-291
Shadiack AM, Hart RP, Carlson CD, Jonakait GM 1993 Interleukin-1 induces substance P in sympathetic ganglia through the induction of leukemia inhibitory factor (LIF). J Neurosci 13:2601-2609
Hurst S, Collins SM 1993 Interleukin-1/3 modulation of norepinephrine release from rat myenteric nerves. Am J Physiol 264:
G30-G35
Niijima A, Hori T, Aou S, Oomura Y 1991 The effects of interleukin-1 beta on the activity of adrenal, splenic and renal sympathetic nerves in the rat. J Auton Nerv Syst 36:183-192
Shimizu N, Hori T, Nakane H1994 An interleukin-1 beta-induced
noradrenaline release in the spleen is mediated by brain corticotropin-releasing factor: an in vivo microdialysis study in conscious
rats. Brain Behav Immun 8:14-23
Terao A, Oikawa M, Saito M 1994 Tissue-specific increase in
norepinephrine turnover by central interleukin-1, but not by interleukin-6, in rats. Am J Physiol 266:R400-R404
Vriend CY, Zuo L, Dyck DG, Nance DM, Greenberg AH 1993
Central administration of interleukin-1 beta increases norepinephrine turnover in the spleen. Brain Res Bull 31:39-42
Rogausch H, del Rey A, Kabiersch A, Besedovsky HO 1995 In-
100
458.
459.
460.
461.
462.
463.
464.
465.
466.
467.
468.
469.
470.
471.
472.
473.
474.
475.
476.
477.
478.
479.
480.
481.
482.
BESEDOVSKY AND DEL REY
terleukin-1 increases splenic blood flow by affecting the sympathetic vasoconstrictor tonus. Am J Physiol, 268:R902-R908
Dantzer R 1994 Cytokines and behavior. The Physiologist 37:
A4-A5 (Abstract)
Dunn AJ, Welch J 1991 Stress- and endotoxin-induced increases in
brain tryptophan and serotonin metabolism depend on sympathetic nervous system activity. J Neurochem 57:1615-1622
Gozes Y, Moskowitz MA, Strom TB, Gozes I 1982 Conditioned
media from activated lymphocytes maintain sympathetic neurons
in culture. Brain Res 282:93-97
Selmaj KW, Farooq M, Noreton WT, Raine CS, Brosnan CF 1990
Proliferation of astrocytes in vitro in response to cytokines: a primary role for tumor necrosis factor. J Immunol 144:129-135
Kamegei M, Niijima K, Kunishita T, Nishizawa M, Ogawa M,
Araki M, Ueki A, Konishi Y, Tabira T1990 Interleukin 3 as a tropic
factor for central cholinergic neurons in vitro and in vivo. Neuron
2:429-436
Jonakait GM 1993 Neural interactions in sympathetic ganglia.
Trends Neurosci 16:419-423
Lindholm D, Heumann R, Meyer M, Thoenen H 1987 Interleukin-1 regulates synthesis of nerve growth factor in non-neuronal
cells of rat sciatic nerve. Nature 330:658-659
Patterson PH, Nawa H 1993 Neuronal differentiation factors/cytokines and synaptic plasticity. Cell 72:123-137
Benveniste EN 1992 Cytokines: influence on glial cell gene expression and function. Neuroimmunoendocrinology 52:106-153
Merrill JE 1992 Tumor necrosis factor alpha, interleukin 1 and
related cytokines in brain development: normal and pathological.
Dev Neurosci 14:1-10
Kluger MJ 1991 Fever: role of pyrogens and cryogens. Physiol Rev
71:93-127
Rothwell NJ1991 Functions and mechanisms of interleukin 1 in the
brain. Trends Pharmacol Sci 12:430-436
Blatteis CM 1992 The OVLT: the interface between the brain and
circulating pyrogens? In: Bartfai T, Ottoson D (eds) Neuro-immunology of Fever. Pergamon Press, New York, pp 167-176
Plata Salaman CR 1989 Immunomodulators and feeding regulation: a humoral link between the immune and nervous system.
Brain Behav Immun 3:193-213
Nistico G, De Sarro G 1991 Behavioral and electrocortical spectrum power effects after microinfusion of lymphokines in several
areas of the rat brain. Ann NY Acad Sci 621:119-134
Opp MR, Postlethwaite AE, Seyer JM, Krueger JM 1992 Interleukin 1 receptor antagonist blocks somnogenic and pyrogenic
responses to an interleukin 1 fragment. Proc Natl Acad Sci USA
89:3726-3730
Dray A, Bevan S1993 Inflammation and hyperalgesia: highlighting
the team effort. Trends Pharmacol Sci 14:287-290
Kita A, Imano K, Nakamura H 1993 Involvement of corticotropinreleasing factor in the antinociception produced by interleukin-1 in
mice. Eur J Pharmacol 237:317-322
Kent S, Bluthe RM, Kelley KW, Dantzer R1992 Sickness behavior
as a new target for drug development. Trends Pharmacol Sci 13:
24-28
Dyck DG, Greenberg AH 1991 Immunological tolerance as a conditioned response: dissecting the brain-immune pathways In: Ader
R, Felten D, Cohen N (eds) Psychoneuroimmunology, ed 2. Academic Press Inc, New York, pp 663-684
Kent S, Bluthe RM, Dantzer R, Hardwick AJ, Kelley KW,
Rothwell NJ, Vannice JL 1992 Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1. Proc
Natl Acad Sci USA 89:9117-9120
Sundar SK, Cierpial MA, Kilts C, Ritchie JC, Weiss JM 1990 Brain
IL-1-induced immunosuppression occurs through activation of
both pituitary-adrenal axis and sympathetic nervous system by
corticotropin-releasing factor. J Neurosci 10:3701-3706
Beisel WR 1977 Magnitude of the host nutritional response to
infection. Am J Clin Nutr 30:1236-1247
Filkin JP, Yelich RM 1982 Mechanism of hyperinsulinemia after
reticuloendothelial system phagocytosis. Am J Physiol 242:E115E120
Miller SL, Wallace RJ, Musher DM, Septimus EJ, Kohl S, Baughn
483.
484.
485.
486.
487.
488.
489.
490.
491.
492.
493.
494.
495.
496.
497.
498.
499.
500.
501.
502.
503.
504.
Vol. 17, No. 1
RE 1980 Hypoglycemia as a manifestation of sepsis. Am J Med
68:649-653
Powanda MC, Bostian KA, Diterman RW, Fee WG, Fowler JP,
Hauer EC, White JD 1980 Phagocytosis and the metabolic sequelae
of infection. J Reticuloendothel Soc 27:67-82
Sidey FM, Wardlaw AC, Furman BL1987 Hypoglycemia and acute
stress-induced hyperinsulinemia in mice infected with Bordetella
pertusis or treated with pertusis toxin. J Endocrinol 112:113-122
Riley V, Fitzmaurice MA, Spackman DH 1981 Psychoneuroimmunologic factors in neoplasia: studies in animals. In: Ader R (ed)
Psychoneuroimmunology. Academic Press, New York, pp 31-102
Beutler B, Milsark IW, Cerami AC 1985 Cachectin tumor necrosis
factor: production, distribution and metabolic fate in vivo. J Immunol 135:3972-3977
del Rey A, Besedovsky H 1987 Interleukin 1 affects glucose homeostasis. Am J Physiol 253:R794-R798
Durum SK, Oppenheim JJ, Neta R 1990 Immunophysiologic role
of interleukin 1. In: Oppenheim JJ, Shevach EM (eds) Immunophysiology: The Role of Cells and Cytokines in Immunity and
Inflammation. Oxford University Press Inc, New York, pp 210-225
Rothwell NJ 1989 CRF is involved in the pyrogenic and thermogenic effects of interleukin 1/3 in the rat. Am J Physiol 256:E111E115
Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S,
Milsark IW, Hairi RJ, Fahey TJ, Zentella A, Albert JD, Cerami A,
Shires GT 1986 Shock and tissue injury induced by recombinant
human cachectin. Science 234:470-474
Flores EA, Bistrian BR, Pomposelli JJ, Dinarello CA, Blackburn
GL, Istfan NW 1989 Infusion of tumor necrosis factor/cachectin
promotes muscle catabolism in the rat. A synergistic effect with
interleukin 1. J Clin Invest 83:1614-1622
Lang CH, Dobrescu C1991 Gram-negative infection increases noninsulin-mediated glucose disposal. Endocrinology 128:645-653
del Rey A, Besedovsky HO 1989 Antidiabetic effects of Interleukin-1. Proc Natl Acad Sci USA 86:5943-5947
Hotamisligil GS, Shargill NS, Spiegelman BM 1993 Adipose expression of tumor necrosis factor-a: direct role in obesity-linked
insulin resistance. Science 259:87-91
Lang CH, Dobrescu C, Bagby GJ 1992 Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic
glucose output. Endocrinology 130:43-52
Wogensen L, Helqvist S, Pociot F, Johannesen J, Reimers J,
Mandrup Poulsen T, Nerup J 1990 Intra-peritoneal administration
of interleukin-1 beta induces impaired insulin release from the
perfused rat pancreas. Autoimmunity 7:1-12
Uehara A, Okumura T, Kumei Y, Takasugi Y, Namiki M 1991
Indomethacin reverses interleukin-1-induced hyperinsulinemia in
conscious and freely moving rats. Eur J Pharmacol 192:185-187
Shimizu H, Uehara Y, Shimomura Y, Negishi M, Fukatsu A 1990
Inhibited insulin secretion by recombinant human interleukin-1
beta in adrenalectomized rats: involvement of prostaglandin. Biochem Biophys Res Commun 173:1280-1286
Wogensen L, Helqvist S, Pociot F, Johannesen J, Reimers J,
Mandrup-Poulsen T, Nerup J1990 Intra-peritoneal administration
of interleukin-lb induces impaired insulin release from the perfused rat pancreas. Autoimmunity 7:1-12
Besedovsky HO, del Rey A 1990 Metabolic and endocrine actions
of interleukin-1. Effects on insulin-resistant animals. Ann NY Acad
Sci 594:214-221
Besedovsky HO, del Rey A 1989 Interleukin-1 and glucose homeostasis, an example of the biological relevance of immune-neuroendocrine interactions. Horm Res 31:94-99
Hill MR, Stith RD, McCallum RE 1988 Human recombinant IL-1
alters glucocorticoid receptor function in Reuber hepatoma cells.
J Immunol 141:1522-1528
Garcia-Welsh A, Schneiderman JS, Baly DL 1990 Interleukin-1
stimulates glucose transport in the rat adipose cells. Evidence for
receptor discrimination between IL-1 beta and alpha. FEBS Lett
269:421-424
Taylor DJ, Faragher EB, Evanson JM 1992 Inflammatory cytokines
stimulate glucose uptake and glycolysis but reduce glucose oxidation in human dermal fibroblasts in vitro. Circ Shock 37:105-110
February, 1996
IMMUNE-NEURO-ENDOCRINE INTERACTIONS
505. Filkins JP 1980 Endotoxin-enhanced secretion of macrophage insulin-like activity. J Reticuloendothel Soc 27:507-511
506. del Rey A, Besedovsky H 1992 Metabolic and neuroendocrine
effects of proinflammatory cytokines. Eur J Clin Invest 22:10-15
507. Kuriyama K, Hori T, Mori T, Nakashima T 1990 Actions of interferon-a and interleukin-1/3 on the glucose-responsive neurons in
the ventromedial hypothalamus. Brain Res Bull 24:803-810
508. Schauenstein K, Faessler R, Dietrich H, Schwarz S, Kroemer G,
Wick G 1987 Disturbed immune-endocrine communication in autoimmune disease. Lack of corticosterone response to immune
signals in Obese Strain chickens with spontaneous autoimmune
thyroiditis. J Immunol 139:1830-1833
509. Saphier D 1989 Neurophysiological and endocrine consequences
of immune activity. Psychoneuroendocrinology 14:63-87
510. Shek PN, Sabiston BH 1983 Neuroendocrine regulation of immune processes: changes in circulating corticosterone levels induced by the primary antibody response in mice. Int J Immunopharmacol 5:23-33
511. Stenzel Poore M, Vale WW, Rivier C 1993 Relationship between
antigen-induced immune stimulation and activation of the hypothalamic-pituitary-adrenal axis in the rat. Endocrinology 132:13131318
512. Dunn AJ, Powell ML, Moreshead WV, Gaskin JM, Hall NR 1987
Effect of Newcastle Disease Virus administration to mice on the
metabolism of cerebral monoamines, plasma corticosterone and
lymphocyte proliferation. Brain Behav Immun 1:216-230
513. Nakano K, Suzuki S, Oh C1987 Significance of increased secretion
of glucocorticoids in mice and rats injected with bacterial endotoxin. Brain Behav Immun 1:159-172
514. de Rijk R, van Rooijen N, Besedovsky H, del Rey A, Berkenbosch
F 1991 Selective depletion of macrophages prevents pituitary-adrenal activation in response to subpyrogenic but not to pyrogenic
doses of bacterial endotoxin in rats. Endocrinology 129:330-338
515. Besedovsky HO, del Rey A, Sorkin E, Schardt M, Normann S,
Baumann J, Girard J1985 Changes in plasma hormone profile after
tumor transplantation into syngeneic and allogeneic rats. Int J
Cancer 36:209-216
516. Normann S, Besedovsky HO, Schardt M, del Rey A 1988 Hormonal changes following tumor transplantation and the relationship of corticosterone to tumor induced anti-inflammation. Int J
Cancer 41:850-854
517. Besedovsky HO, del Rey A, Normann S 1989 Host endocrine
responses during tumor growth. In: Mitchell MS (ed) Immunity to
Cancer II. Alan R Liss Inc, New York, pp 203-213
518. Normann S, Besedovsky HO, Schardt M, del Rey A 1988 Interactions between endogenous glucocorticoids and inflammatory
responses in normal and tumor bearing mice: role of T cells.
J Leukocyte Biol 44:551-558
519. Besedovsky HO, Sorkin E, Keller M 1978 Changes in the concentration of corticosterone in the blood during skin-graft rejection
in the rat. J Endocrinol 76:175-176
520. Zakarian S, Eleazar MS, Silvers WK 1989 Regulation of proopiomelanocortin biosynthesis and processing by transplantation
immunity. Nature 339:553-556
521. Reichlin S, Glaser RJ1958 Thyroid function in experimental streptococcal pneumonia in rat. J Exp Med 107:219-236
522. Neidhart M, Larson DF 1990 Freund's complete adjuvant induces
ornithine decarboxylase activity in the central nervous system of
male rats and triggers the release of pituitary hormones. J Neuroimmunol 26:97-105
523. del Rey A, Besedovsky HO, Sorkin E, Da Prada M, Arrenbrecht
S 1981 Immunoregulation mediated by the sympathetic nervous
system II. Cell Immunol 63:329-334
524. del Rey A, Besedovsky HO, Sorkin E, Da Prada M, Bondiolotti
P 1982 Sympathetic immunoregulation: difference between highand low-responder animals. Am J Physiol 242:R30-R33
525. Besedovsky HO, del Rey A, Sorkin E 1985 Immunoneuroendocrine interactions. J Immunol 135:750s-754s
526. Mackenzie FJ, Leonard JP, Cuzner ML 1989 Changes in lymphocyte b-adrenergic receptor density and noradrenaline content of the
spleen are early indicators of immune reactivity in acute experimental allergic encephalomyelitis in the Lewis rat. J Neuroimmunol 23:93-100
101
527. Esquifino AI, Cardinali DP 1994 Local regulation of the immune
response by the autonomic nervous system. Neuroimmunomodulation 1:265-273
528. Besedovsky HO, Sorkin E, Felix D, Haas H 1977 Hypothalamic
changes during the immune response. Eur J Immunol 7:323-325
529. Saphier D, Abramsky O, Mor G, Ovadia H 1987 Multiunit electrical activity in conscious rats during an immune response. Brain
Behav Immun 1:40-51
530. Carlson SL, Felten DL, Livnat S, Felten SY 1987 Alterations of
monoamines in specific central autonomic nuclei following immunization in mice. Brain Behav Immun 1:52-63
531. Masek K, Horak P, Kadlec O, Flegel M 1989 The interactions
between neuroendocrine and immune systems at the receptors
level. The possible role of serotonergic system. In: Hadden JW,
Masek K, Nistico G (eds) Interactions among CNS, Neuroendocrine
and Immune Systems. Pythagora Press, Rome, pp 225-234
532. Pearse AGE, Takor Takor T 1979 Embryology of the diffuse neuroendocrine system and its relationship to the common peptides.
Fed Proc 38:2288-2294
533. Polak JM, Bloom SR 1986 Regulatory peptides of the gastrointestinal and respiratory tracts. Arch Int Pharmacodyn 280:16-49
534. Ottaway CA, Lewis DL, Asa SL 1987 Vasoactive intestinal peptide
containing nerves in Peyer's patches. Brain Behav Immun 1:148158
535. Geenen V, Defresne MP, Robert F, Legros JJ, Franchimont P,
Boniver J1988 The neurohormonal thymic microenvironment: immunocytochemical evidence that thymic nurse cells are neuroendocrine cells. Neuroendocrinology 47:365-368
536. Vedeler CA 1987 Demonstration of Fcg receptors on human peripheral nerve fibers. J Neuroimmunol 15:207-216
537. Wekerle H, Linington C, Lassmann H, Meyermann R 1986 Cellular immune reactivity within the CNS. Trends Neurosci 9:271277
538. Hickey WF, Hsu BL, Kimura H 1991 T lymphocyte entry into the
central nervous system. J Neurosci Res 28:254-260
539. Bienenstock J, Blennerhassett M, Kakuta Y, MacQueen G,
Marshall J, Perdue M, Siegel S, Tsuda T, Denburg J, Stead R1989
Evidence for central and peripheral nervous system interaction
with mast cells. In: Galli SJ, Austen KF (eds) Mast Cell and Basophil
Differentiation and Function in Health and Disease. Raven Press,
New York, pp 275-284
540. Collins SM, Hurst SM, Main C, Stanley E, Khan I, Blennerhassett
P, Swain M1992 Effect of inflammation of enteric nerves. Cytokineinduced changes in neurotransmitter content and release. Ann NY
Acad Sci 664:415-424
541. Freier S, Eran M, Faber J 1987 Effect of cholecystokinin and of its
antagonist, of atropine, and of food on the release of immunglobulin A and immunglobulin G specific antibodies in the rat intestine.
Gastroenterology 93:1242-1246
542. Besedovsky HO, del Rey A, Sorkin E, Burri R, Honegger CG,
Schlumpf M, Lichtensteiger W 1987 T lymphocytes affect the
development of sympathetic innervation of mouse spleen. Brain
Behav Immun 1:185-193
543. Breneman SM, Moynihan JA, Grota LJ, Felten DL, Felten SY 1993
Splenic norepinephrine is decreased in MRL-lpr/lpr mice. Brain
Behav Immun 7:135-143
544. Leonard JP, MacKenzie FJ, Patel HA, Cuzner ML 1991 Hypothalamic noradrenergic pathways exert an influence on neuroendocrine and clinical status in experimental autoimmune encephalomyelitis. Brain Behav Immun 5:328-338
545. Wick G, Hu Y, Schwarz S, Kroemer G 1993 Immunoendocrine
communication via the hypothalamus-piruitary-adrenal axis in autoimmune diseases. Endocr Rev 14:539-563
546. Billingham RE, Krohn PL, Medawar PB 1951 Effect of cortisone on
survival of skin homografts in rabbits. Br Med J 1:1157-1163
547. Medawar PB, Sparrow EM 1956 The effect of adrenocortical hormones, adrenocorticotrophic hormone and pregnancy on skin
transplantation immunity in mice. J Endocrinol 14:240-256
548. Luster MI, Germolec DR, Clark G, Wiegand G, Rosenthal GJ1988
Selective effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and corticosteroid on in vitro lymphocyte maturation. J Immunol 140:928935
549. Dennis G, June CH, Mizuguchi J, Ohara J, Withespoon K,
102
550.
551.
552.
553.
554.
555.
556.
557.
558.
559.
560.
561.
562.
BESEDOVSKY AND DEL REY
Finkelman FD, McMillan V, Mond JJ 1987 Glucocorticoids suppress calcium mobilization and phospolipid hydrolysis in anti-Igantibody-stimulated B cells. J Immunol 139:2516-2523
Fauci AS, Pratt KR, Whalen G 1977 Activation of human B lymphocytes. IV. Regulatory effects of corticosteroids on the triggering
signal in the plaque forming cell response of human peripheral
blood B lymphocytes to polyclonal activation. J Immunol 119:598603
Besedovsky HO, del Rey A, Sorkin E 1979 Antigenic competition
between horse and sheep red blood cells as a hormone-dependent
phenomenon. Clin Exp Immunol 37:106-113
Hirschberg H, Hirschberg T, Nausiainen H, Braathen LR, Joffe E
1982 The effects of corticosteroid on the antigenic presentation
properties of human monocytes and endothelial cells. Clin Immunol Immunopathol 23:577-585
Bradley LM, Mishell RI1982 Selective protection of murine thymic
helper T cells from glucocorticoid inhibition by macrophage-derived mediators. Cell Immunol 73:115-127
Fairchild SS, Shannon K, Kwan E, Mishell RI 1984 T cell-derived
glucosteroid response-modifying factor (GRMFT): a unique lymphokine made by normal T lymphocytes and a T cell hybridoma.
J Immunol 132:821-827
Kam JC, Szefler J, Surs W, Sher ER, Leung DYM 1993 Combination IL-2 and IL-4 reduces glucocorticoid receptor-binding affinity and T cell response to glucocorticoids. J Immunol 151:34603466
Tokuda S, Trujillo LC, Nofchissey RA 1984 Hormonal regulation
of the immune response. In: Cooper EL (ed) Stress, Immunity and
Aging. Marcel Dekker Inc, New York, pp 141-155
Helderman JH, Strom TB, Dupuy-d'Angeac A 1979 A close relationship between cytotoxic T lymphocytes generated in the mixed
lymphocyte culture and insulin receptor-bearing lymphocytes: enrichment by density gradient centrifugation. Cell Immunol 46:247258
Fitch FW, Stejskal R, Rowley DA 1969 Histologic localization of
hemolysin-containing cells. In: Fiore-Donati L, Hanna Jr MG (eds)
Advances in Experimental Medicine and Biology. Lymphatic Tissue and Germinal Centers in Immune Response. Plenum Press,
New York, vol 5:223-231
Anderson A 1990 Structure and organization of the lymphatic
system. In: Oppenheim JJ, Shevach EM (eds) Immunophysiology.
The Role of Cells and Cytokines in Immunity and Inflammation.
Oxford University Press, New York, pp 14-45
Sternberg EM, Hill JM, Chrousos GP, Kamilaris T, Listwak SJ,
Gold PW, Wilder RL 1989 Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci
USA 86:2374-2378
Neek G, Federlin K, Graef V, Rusch D, Schmidt KL 1990 Adrenal
secretion of cortisol in patients with rheumatoid arthritis. J Rheumatol 17:24-29
Brezinschek HP, Faessler R, Klocker H, Kroemer G, Sgonc R,
Dietrich H, Jakober R, Wick G 1990 Analysis of the immuneendocrine feedback loop in the avian system and its alteration in
563.
564.
565.
566.
567.
568.
569.
570.
571.
572.
573.
574.
575.
576.
577.
578.
Vol. 17, No. 1
chicken with spontaneous autoimmune thyroiditis. Eur J Immunol
20:2155-2159
Hu Y, Dietrich H, Herold M, Heinrich PC, Wick G 1993 Disturbed
immune-endocrine communication via the hypothalamus-pituitary-adrenal axis in autoimmune disease. Int Arch Allergy
Immunol 102:232-241
Levine S, Sowinski R, Steinetz B 1980 Effects of experimental
allergic encephalomyelitis on thymus and adrenal: relation to remission and relapse (40961). Proc Soc Exp Biol Med 165:218-224
MacPhee IAM, Antoni FA, Mason WD1989 Spontaneous recovery
of rats from experimental allergic encephalomyelitis is dependent
on regulation of the immune system by endogenous adrenal corticosteroids. J Exp Med 169:431-445
Dinarello CA 1992 The role of interleukin-1 in host responses to
infectious diseases. Infect Agents Dis 1:227-236.
Van Zee KJ, Kohno T, Fischer E, Rock CS, Moldawer LL, Lowry
SF 1992 Tumor necrosis factor soluble receptors circulate during
experimental and clinical inflammation and can protect against
excessive tumor necrosis factor alpha in vitro and in vivo. Proc Natl
Acad Sci USA 89:4845-4849
Fiedler VB, Loof I, Sander E, Voehringer V, Galanos C, Fournel
MA 1992 Monoclonal antibody to tumor necrosis factor-alpha prevents lethal endotoxin sepsis in adult rhesus monkeys. J Lab Clin
Med 120:574-588
Arend WP 1993 Interleukin-1 receptor antagonist. Adv Immunol
54:167-227
Moldawer LL 1993 Interleukin-1, TNF alpha and their naturally
occuring antagonists in sepsis. Blood Purif 11:128-133
Hinshaw LB, Emerson Jr TE, Taylor Jr FB, Chang AC, Duerr M,
Peer GT, Flournoy DJ, White GL, Kosanke SD, Murray CK, Xu
K, Passey RD, Tournel MA 1992 Lethal Staphylococcus aureusinduced shock in primates: prevention of death with anti-TNF
antibody. J Trauma 33:568-573
Silva AT, Cohen J 1992 Role of interferon-gamma in experimental
gram-negative sepsis. J Infect Dis 166:331-335
Gottschall PE, Katsuura G, Arimura A 1989 Interleukin-1 beta is
more potent than interleukin-1 alpha in suppressing follicle-stimulating hormone-induced differentiation of ovarian granulosa
cells. Biochem Biophys Res Commun 163:764-770
Kalra PS, Sahu A, Kalra SP 1990 Interleukin-1 inhibits the ovarian
steroid-induced luteinizing hormone surge and release of hypothalamic luteinizing hormone-releasing hormone in rats. Endocrinology 126:2145-2152
Rivier C, Vale W 1990 Cytokines act within the brain to inhibit
luteinizing hormone secretion and ovulation in the rat. Endocrinology 127:849-856
Besedovsky HO, Sorkin E 1974 Involvement of the thymus in
female sexual maturation. Nature 249:356-358
Pedernera EA, Romano M, Besedovsky HO, Aguilar MC1980 The
bursa of Fabricius is required for normal endocrine development
in chicken. Gen Comp Endocrinol 42:413-419
Zhang Y, Proenca R, Maffel M, Barone M, Leopold L, Friedman
JM 1994 Positional cloning of the mouse obese gene and its human
homologue. Nature 372:425-432