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Endocrinology 149(8):4080 – 4085
Copyright © 2008 by The Endocrine Society
doi: 10.1210/en.2008-0327
Role and Regulation of Adipokines during ZymosanInduced Peritoneal Inflammation in Mice
Maria Pini, Melissa E. Gove, Joseph A. Sennello, Jantine W. P. M. van Baal, Lawrence Chan,
and Giamila Fantuzzi
Department of Kinesiology and Nutrition (M.P., M.E.G., J.A.S., J.W.P.M.v.B., G.F.), University of Illinois at Chicago,
Chicago, Illinois 60612; and Department of Molecular and Cellular Biology (L.C.), Baylor College of Medicine, Houston,
Texas 77030
Adipokines, cytokines mainly produced by adipocytes, are
active participants in the regulation of inflammation. Administration of zymosan (ZY) was used to investigate the regulation and role of adipokines during peritonitis in mice. Injection of ZY led to a significant increase in leptin levels in both
serum and peritoneal lavage fluid, whereas a differential
trend in local vs. systemic levels was observed for both resistin
and adiponectin. The role of leptin in ZY-induced peritonitis
was investigated using leptin-deficient ob/ob mice, with and
without reconstitution with exogenous leptin. Leptin deficiency was associated with delayed resolution of peritoneal
inflammation induced by ZY, because ob/ob mice had a more
pronounced cellular infiltrate in the peritoneum as well as
A
DIPOSE TISSUE IS not simply an inert storage depot
for lipids but is also important in the integration of
endocrine, metabolic, and inflammatory signals (1–3). Adipokines, such as leptin, adiponectin (APN) and resistin are
active modulators of inflammation (4 –9). In particular, leptin
is a cytokine-like hormone important in the regulation of
energy-demanding physiological processes, such as hemopoiesis, angiogenesis, wound healing, and the immune and
inflammatory response (1, 10 –18). During infection and inflammation, the increase in leptin production has strongly
suggested that leptin is part of the cytokine cascade that
modulates the immune response (19, 20). Leptin protects T cells
from apoptosis and modulates T-cell proliferation and activation, macrophage phagocytosis, and expression of adhesion
molecules (21). However, both pro- and antiinflammatory effects have been described for leptin. In models of T-cell-mediated inflammation, such as experimental allergic encephalomyelitis, collagen-induced arthritis, and autoimmune hepatitis,
leptin-deficient ob/ob mice are protected (22, 23). In contrast, in
models in which inflammation is independent of adaptive immunity, such as zymosan (ZY)-induced arthritis or administration of endotoxin [lipopolysaccharide (LPS)], leptin appears
to exert antiinflammatory properties (12, 24).
The role of APN in regulating inflammatory responses also
First Published Online May 1, 2008
Abbreviations: APN, Adiponectin; CXCL2, chemokine (C-X-C motif)
ligand 2; KO, knockout; MW, molecular weight; PLF, peritoneal lavage
fluid; WT, wild type; ZY, zymosan.
Endocrinology is published monthly by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
higher and prolonged local and systemic levels of IL-6, TNF␣,
IL-10, and chemokine (C-X-C motif) ligand 2 compared with
wild-type mice. Reconstitution with exogenous leptin exacerbated the inflammatory infiltrate and systemic IL-6 levels in
ob/ob mice while inhibiting production of TNF␣, IL-10, and
chemokine (C-X-C motif) ligand 2. In contrast with the important role of leptin in regulating each aspect of ZY-induced
peritonitis, adiponectin deficiency was associated only with a
decreased inflammatory infiltrate, without affecting cytokine
levels. These findings point to a complex role for adipokines
in ZY-induced peritonitis and further emphasize the interplay between obesity and inflammation. (Endocrinology
149: 4080 – 4085, 2008)
appears to be tissue and context specific (25–27). The biology of
APN has mostly been investigated in the context of insulin
sensitivity and atherosclerosis (28 –30). A strong epidemiological relationship between low circulating APN and diabetes,
metabolic syndrome, and cardiovascular disease has been reported (1). In accordance, several antiinflammatory effects have
been described for APN, including inhibition of TNF␣ production and activity, inhibition of nuclear factor-␬B activation, and
induction of antiinflammatory cytokines as well as down-regulation of adhesion molecules (17, 31–37). Based on these observations and on the protective role of APN in cardiovascular
disease, this adipokine is generally considered as an antiinflammatory molecule. However, several reports demonstrated
that APN can have proinflammatory properties (38 – 42).
To better understand the regulation of adipokines and the
role these proteins play in inflammation, we challenged mice
with ZY, a cell wall product of the yeast Saccharomyces
cerevisiae (43). ZY is a potent stimulator of innate immunity, activating macrophages mostly through Toll-like receptor 2 (TLR2), although other receptors are also involved
(44 –50). We first evaluated the regulation of adipokines during ZY-induced peritonitis. Second, to better understand the
role played by leptin and APN in ZY-induced peritonitis, we
investigated the effect of ZY-induced inflammation in leptindeficient ob/ob mice as well as APN knockout (KO) mice.
Materials and Methods
Mice
Care of mice followed institutional guidelines under protocols approved by the University of Illinois at Chicago. All mice used in these
experiments had a C57BL6 background. Adiponectin KO mice were
generated as previously described (51). Mice heterozygous for APN
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Pini et al. • Adipokines and Peritoneal Inflammation
Mice were injected ip with 100 mg/kg of a sterile suspension of ZY
(Sigma Chemical Co., St. Louis, MO) in saline. The dose of ZY was
chosen in accord with previously published data (52, 53). Control mice
received an ip injection of saline. All injections were performed between
0900 and 1100 h. Approximately 0.5 ml blood was collected from the
retroorbital plexus under isoflurane anesthesia at different time points
after ZY injection, and serum was prepared. Mice were euthanized by
cervical dislocation immediately after bleeding, and peritoneal lavage
fluid (PLF) was collected, as follows. Mice were instilled with 5 ml
ice-cold sterile RPMI in the peritoneal cavity, followed by gentle manual
massage and removal of 3 ml fluid. The PLF was centrifuged, supernatants were collected for cytokine measurement, and the cells were
resuspended in 1 ml RPMI and counted on a hemocytometer.
Cytokine and adipokine measurement
Chemokine (C-X-C motif) ligand 2 (CXCL2), leptin, APN, and resistin
levels were measured using ELISA kits from R&D Systems. TNF␣, IL-6,
and IL-10 levels were measured using ELISA kits from e-Bioscience (San
Diego, CA). The distribution of APN multimeric forms was examined
in serum and PLF after fractionation as previously described (20).
Statistical analysis
Data are expressed as mean ⫾ sem. The statistical significance of
differences between treatment and control groups was determined by
factorial ANOVA. Statistical analyses were performed using the XLStat
software (Addinsoft, Brooklyn, NY).
Results
Effect of ZY administration on adipokine levels
To investigate the effect of ZY-induced peritoneal inflammation on systemic and local adipokine levels, wild-type
(WT) mice received an ip injection of ZY or vehicle. Basal
levels of leptin, resistin, and APN were 20-, 7-, and 1000-fold
higher in serum than in PLF, respectively (Fig. 1, A–C).
Administration of ZY induced a significant increase in both
circulating and PLF leptin at 6 h, with levels returning to
baseline by 24 h (Fig. 1A). In contrast, a differential trend in
local vs. systemic levels was observed for both resistin and
APN. As shown in Fig. 1B, although serum resistin levels
were not significantly altered at any time point after ZY
administration, PLF resistin showed a 2-fold increase at 2 h
followed by a 3-fold peak at 6 h, returning to baseline levels
at 24 h. Finally, whereas a statistically significant reduction
in serum APN levels was observed at 2 and 6 h after ZY (58
and 52% reduction, respectively), PLF APN levels did not
change significantly after ZY injection (Fig. 1C). Fractionation of serum and PLF obtained from vehicle and ZY-injected mice demonstrated that the ratio of high to middle-low
molecular weight (MW) APN was not significantly altered by
ZY administration and did not differ between serum and PLF
(data not shown).
leptin (ng/ml)
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*
A
6
***
3
0
resistin (ng/ml)
Induction and evaluation of peritonitis
9
9
B
6
3
*
***
0
APN ( g/ml-ng/ml)
were mated and 6- to 8-wk-old littermates used for each experiment.
Mice were genotyped by PCR of tail DNA, and APN deficiency was
confirmed by measuring serum APN using a specific ELISA (R&D
Systems, Inc., Minneapolis, MN). Age-matched female leptin-deficient
(C57BL/6Job/ob) mice, their lean littermates (⫹/?), and C57BL/6J mice
were obtained from The Jackson Laboratory (Bar Harbor, ME). A group
of ob/ob mice received ip injections of recombinant murine leptin (R&D
Systems) for 5 d (1 mg/kg) before ZY administration.
Endocrinology, August 2008, 149(8):4080 – 4085
9
C
6
***
3
***
0
Saline
2h
6h
24h
FIG. 1. Leptin (A), resistin (B), and APN (C) levels in serum and PLF
after ZY administration. WT mice were injected with ZY or vehicle.
Serum (⽧) and PLF (䡺) were collected at various times for measurement of leptin, resistin, and APN by ELISA. In C, serum APN levels
are expressed as micrograms per milliliter, whereas PLF levels are
expressed as nanograms per milliliter. Data are mean ⫾ SEM of four
to five mice per group. *, P ⬍ 0.05; ***, P ⬍ 0.001 vs. respective vehicle.
Role of leptin in ZY-induced inflammation
To investigate whether leptin and/or obesity plays a role
in modulating inflammation after administration of ZY, the
response of ob/ob mice, with or without leptin replacement,
was compared with that of WT animals. Leptin replacement
in ob/ob mice led to serum leptin levels that were comparable
to those observed in WT mice (serum leptin was 3.3 ⫾ 1.1 vs.
2.1 ⫾ 0.3 ng/ml in WT vs. leptin-injected ob/ob mice, respectively; data are mean ⫾ sem; n ⫽ 3). However, this short
course of leptin replacement did not induce a significant
body weight loss in ob/ob mice (body weight was 47.4 ⫾ 0.4
vs. 47.4 ⫾ 0.7 g in ob/ob vs. leptin-replaced ob/ob mice, respectively; data are mean ⫾ sem; n ⫽ 5). Thus, the group of
leptin-replaced ob/ob mice was obese but had leptin levels
comparable to those of WT mice. This group was used to
differentiate between a direct effect of leptin vs. the effect of
obesity on ZY-induced inflammation.
A significantly higher number of resident cells were
present in the peritoneum of vehicle-injected ob/ob compared with WT mice; reconstitution with recombinant leptin
led to a further increase in the number of peritoneal cells (Fig.
2A). Administration of ZY induced a significantly more pronounced infiltrate in ob/ob compared with WT mice at both
6 and 24 h, with a further increase observed in the group of
ob/ob that had received exogenous leptin (Fig. 2A).
Administration of ZY induced significantly higher levels
of IL-6 in both serum (Fig. 2B) and PLF (Fig. 2C) in ob/ob
compared with WT mice. Although the systemic response
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Endocrinology, August 2008, 149(8):4080 – 4085
25
cells x 106
***
15
10
***
5
*
***
0
50
IL-6 (ng/ml)
temic IL-6 response compared with non-leptin-injected ob/ob
mice without significantly altering PLF IL-6 levels (Fig. 2, B
and C). Thus, administration of leptin enhanced the systemic
IL-6 response of ob/ob mice although not significantly altering local IL-6 levels.
In contrast with its potentiating effects on IL-6 production,
leptin reconstitution of ob/ob mice reduced production of
TNF␣, IL-10, and CXCL2. In fact, a significantly enhanced
and prolonged local response to ZY was observed for each
of the three cytokines in ob/ob compared with WT mice, with
leptin administration significantly dampening the heightened cytokine response of ob/ob mice (Fig. 2, D–F). A similar
trend was observed when serum cytokine levels were measured (not shown).
**
*
A
20
Pini et al. • Adipokines and Peritoneal Inflammation
40
**
B
3
2
1
0
30
*
20
***
***
24h
10
0
Role of leptin in ZY-induced modulation of adipokine levels
IL-6 (ng/ml)
6
C
4
***
2
TNFα (pg/ml)
0
600
D
***
400
***
*
200
**
0
IL-10 (ng/ml)
6
E
***
4
Role of APN in ZY-induced inflammation
*
**
2
The effect of leptin on regulation of APN and resistin levels
after ZY administration was investigated using ob/ob and
leptin-reconstituted ob/ob mice. Leptin administration to
ob/ob mice normalized basal serum APN levels (Fig. 3A).
Although administration of ZY significantly reduced circulating APN in WT mice, as already shown above in Fig. 1C,
no significant change in serum APN was observed in ob/ob
or leptin-replaced ob/ob mice receiving ZY. No significant
changes in PLF APN levels in response to ZY were observed
in any of the three groups (data not shown).
Although ZY did not significantly alter systemic resistin
levels in any of the mice studied (data not shown), the kinetics of the PLF resistin response of ob/ob and leptin-replaced ob/ob mice was significantly prolonged compared
with that of WT mice, which in contrast fully recovered by
24 h (Fig. 3B).
To investigate a potential role for APN in ZY-induced
inflammation, the response of WT and APN KO mice was
compared. Although a significantly reduced inflammatory
infiltrate was observed at 6 and 24 h after ZY in the peritoneal
4
F
**
3
***
2
APN (µg/ml)
CXCL2 (ng/ml)
0
12
A
***
*
8
4
1
0
Saline
6h
24h
FIG. 2. Effect of ZY in ob/ob mice. WT (⽧), ob/ob (e) and leptin-injected
ob/ob (f) mice were injected with ZY or vehicle. Cellular infiltrate (A)
as well as serum IL-6 (B) and PLF IL-6 (C), TNF␣ (D), IL-10 (E), and
CXCL2 (F) were evaluated at the indicated time points. The inset in
B shows IL-6 levels at 24 h after ZY. Data are mean ⫾ SEM of four to
five mice per group. *, P ⬍ 0.05; **, P ⬍ 0.01; ***, P ⬍ 0.001 vs. WT.
◊◊, P ⬍ 0.01; ◊◊◊, P ⬍ 0.001 vs. ob/ob.
was enhanced at both 6 and 24 h, PLF IL-6 levels were
significantly higher in ob/ob compared with WT mice only at
the later time point (Fig. 2, B and C). Administration of
exogenous leptin to ob/ob mice further increased the sys-
resistin (ng/ml)
0
2
B
***
***
1
0
Saline
6h
24h
FIG. 3. APN (A) levels in serum and resistin (B) levels in PLF after
ZY. WT (⽧), ob/ob (䡺), and leptin-injected ob/ob (f) mice were injected
ip with ZY or vehicle. Circulating APN (A) as well as PLF resistin (B)
were evaluated at the indicated time points. Data are mean ⫾ SEM of
four to five mice per group. *, P ⬍ 0.05; ***, P ⬍ 0.001 vs. WT. ◊, P ⬍
0.05 vs. ob/ob.
Pini et al. • Adipokines and Peritoneal Inflammation
Endocrinology, August 2008, 149(8):4080 – 4085
cavity of APN KO compared with WT mice (Fig. 4), serum
and PLF cytokines, leptin, and resistin levels were not significantly different between WT and APN KO mice at any of
the time points analyzed (data not shown).
Discussion
The aim of the present study was to investigate the role of
leptin and APN in regulating inflammation during ZY-induced
peritonitis. We demonstrate that adipokines are differentially
modulated after administration of ZY and that although leptin
plays a major role in regulating the inflammatory response to
ZY, APN deficiency has only a minor effect.
Although leptin and resistin levels were in the same order
of magnitude in serum and PLF on untreated lean mice,
APN⬘s concentration was approximately 1000-fold lower in
PLF compared with serum. This major difference between
serum and PLF APN levels is similar to that previously
reported for other body fluids, such as bronchoalveolar lavage and cerebrospinal fluid (54, 55). Mechanisms including
active exclusion, increased degradation, and selective transport of low vs. high MW APN have been proposed to explain
the low levels of APN present in cerebrospinal fluid (56, 57).
Whether these mechanisms are responsible for maintaining
low levels of APN in PLF remains to be investigated, although our data obtained from fractionation studies indicate
that the distribution of middle/low vs. high MW APN did
not significantly differ between serum and PLF.
In agreement with previous data demonstrating that acute
inflammation reduces circulating APN levels (58, 59), we found
a significant reduction in serum APN during ZY-induced peritonitis. Interestingly, although inflammation had a profound
effect on systemic APN, no significant changes were observed
in the amount of APN present in PLF after ZY injection. Lack
of modulation at the local level was unique to APN, because
each of the other adipokines and cytokines measured showed
more pronounced changes locally than systemically in response
to ZY. These results, together with data indicating a role for
leptin and obesity in regulating APN levels during inflammation (see Fig. 3), point to a complex regulation of APN production and compartmentalization in the course of inflammatory
responses.
The role and regulation of APN during inflammation is
multifaceted and highly dependent upon the stimuli and
tissues involved (60). During ZY-induced peritonitis, endogenous APN did not play a crucial role in modulating the
inflammatory response. In fact, when compared with WT
mice, APN KO mice had a minor reduction in cellular infiltrate, with no significant changes in terms of cytokine or
cells x 106
12
*
8
*
4083
adipokine levels. These data are in agreement with previous
results obtained by our group using the models of inflammation induced by injection of LPS or concanavalin A and
demonstrating negligible effects of APN deficiency in the
regulation of cytokine production (61).
In contrast with the apparently minor role of APN in the
inflammatory response to ZY, leptin significantly contributed to
modulation of cellular infiltrate and cytokine production. An
overall increase in the inflammatory response to ZY was observed in ob/ob compared with WT mice, including a more
pronounced cellular infiltrate in the peritoneal cavity as well as
higher local and systemic levels of each of the cytokines measured. Furthermore, whereas in WT mice cytokine levels returned to baseline values by 24 h after ZY, a more prolonged
cytokine response, particularly at the local level, was observed
in ob/ob mice, indicating failure to effectively resolve the inflammatory response, in agreement with previous data obtained using the model of ZY-induced arthritis (24). Delayed
resolution of peritoneal inflammation induced by ZY was, however, not secondary to reduced IL-10 production, as previously
suggested for the increased sensitivity of ob/ob mice to LPS (12),
because levels of this antiinflammatory cytokine were highly
elevated in ob/ob mice injected with ZY.
Whereas leptin deficiency was associated with generalized
worsening of the inflammatory response, a selective effect of
reconstitution with exogenous leptin was observed. Administration of leptin further increased the already elevated inflammatory infiltrate and systemic IL-6 levels in ob/ob mice.
Because the schedule of leptin reconstitution used in these
experiments did not induce significant weight loss, exacerbation of these parameters by leptin suggests that obesity,
rather than leptin deficiency, is responsible for the differences between WT and ob/ob mice. In contrast, production
of TNF␣, IL-10, and CXCL2 was significantly reduced by
leptin, indicating that lack of leptin is directly responsible for
the increased production of these mediators in ob/ob mice.
Levels of resistin, which is mainly produced by adipocytes
in mice and by macrophages in humans, are usually increased during active inflammation (62). Although ZY did
not significantly alter systemic resistin levels in mice, local
levels of this cytokine followed kinetics similar to that of the
other cytokines measured. In particular, an overlapping pattern of local response was observed for resistin and IL-6, the
kinetics of production of both being prolonged in ob/ob mice
regardless of administration of exogenous leptin, suggesting
similar mechanisms of regulation for these two cytokines.
In conclusion, our results further extend understanding of
the complex interactions among adipokines, adipose tissue,
and inflammation. We demonstrate that inflammation is an
important modulator of adipokine levels in mice, while at the
same time adipose tissue-derived products exert selective
and potent effects on various parameters of the inflammatory
response.
4
0
Acknowledgments
Saline
6h
24h
FIG. 4. Reduced cellular infiltrate in APN KO mice. WT (⽧) and
APN-KO (〫) mice were injected ip with ZY or vehicle. Cellular infiltrate was evaluated at the indicated time points. Data are mean ⫾ SEM
of four to five mice per group. *, P ⬍ 0.05 vs. APN KO.
Received March 7, 2008. Accepted April 7, 2008.
Address all correspondence and requests for reprints to: Giamila
Fantuzzi, University of Illinois at Chicago, 1919 West Taylor Street MC
517, Chicago, Illinois 60612. E-mail:[email protected].
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Endocrinology, August 2008, 149(8):4080 – 4085
This work was supported by National Institutes of Health Grants
DK061483 and DK068035 (to G.F.) and DK68037 and HL51586 (to L.C.).
Disclosure Statement: The authors have nothing to disclose.
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