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Interleukin-15 (IL-15) Induces IL-8 and Monocyte Chemotactic Protein 1
Production in Human Monocytes
By Raffaele Badolato, Alessandro Negro Ponzi, Maura Millesimo, Luigi D. Notarangelo, and Tiziana Musso
Interleukin-15 (IL-15) is a recently characterized cytokine that
shares many biological activities with IL-2 and interacts with
the b and g components of the IL-2 receptor. Unlike IL-2,
which is secreted only by T cells, IL-15 is expressed preferentially by nonlymphoid tissues, epithelial, and fibroblast cell
lines and by activated monocytes/macrophages. High concentrations of IL-15 have been shown in inflamed joints of
rheumatoid arthritis patients, suggesting a role for IL-15 in
inflammatory diseases where there is recruitment of leukocytes. Although monocytes have been shown to bind IL-15,
its effects on these cells are not defined. In this report we
show that supernatants of monocytes treated with IL-15–
contained chemotactic activity for neutrophils and monocytes which was neutralized by anti-IL-8 or by anti-monocyte
chemotactic protein 1 (MCP-1) antibodies, respectively.
Secretion of IL-8 and MCP-1 proteins is detectable by enzyme-linked immunosorbent assay as early as 6 hours after
stimulation with IL-15. Production of the two chemokines is
correlated with induction by IL-15 of mRNA expression in
monocytes. In addition, IL-8 and MCP-1 induction by IL-15 is
differently regulated by interferon-g (IFN-g) and IL-4. IFN-g
inhibited IL-15–induced IL-8 secretion, but synergized with
IL-15 in MCP-1 induction; whereas IL-4 inhibited both IL-8
and MCP-1 induction by IL-15. These results show that IL15 can stimulate monocytes to produce chemokines that
cause inflammatory cell accumulation. Thus, IL-15 locally
produced at sites of inflammation may play a pivotal role in
the regulation of the leukocyte infiltrate.
q 1997 by The American Society of Hematology.
I
at the site of injection not only of lymphocytes but also of
other mononuclear and of polymorphonuclear cells indicating that their recruitment might be mediated by induction
of other proinflammatory cytokines such as chemokines.6,13
When activated by proinflammatory cytokines such as IL-1,
tumor necrosis factor (TNF), or leukemia inhibitory factor
(LIF), monocytes produce large amounts of chemotactic factors such as IL-8 and monocyte chemotactic protein 1 (MCP1).15-18 These chemoattractants of 7 to 10 kD, that have
heparin-binding properties and ability to bind and activate
seven-transmembrane spanning receptors, induce adhesion
to endothelial cells and chemotaxis of lymphocytes, monocytes, or PMN.15,19-22
Since monocytes have been reported to express binding
sites for IL-15 but the functional significance of this interaction has not been defined, we investigated whether monocytes responded to IL-15 with production of chemotactic
factors.7,23 Here we report that IL-15 stimulates monocytes to
produce MCP-1 and IL-8, two chemokines that specifically
attract monocytes and neutrophils, respectively.
NTERLEUKIN-15 (IL-15), a novel cytokine identified on
the basis of biological activities similar to IL-2, induces
T-cell proliferation, generates cytotoxic effector cells and
lymphokine-activated killer activity in natural killer cells,
causes B-cell proliferation and differentiation, and stimulates
chemotaxis of T cells.1-6 IL-15 also shares with IL-2 the b
and g subunits as common receptor components of their
receptor complexes.1,7-10 However, the IL-15–receptor complex also includes an IL-15-R a-chain, distinct from the IL2R a-chain, that allows high-affinity binding.8,10
IL-15 mRNA is expressed at high levels in lipopolysaccharide (LPS)-activated monocytes, in fibroblasts, epithelial
cell-lines, and in several other nonimmune tissues such as
placenta, skeletal muscle, heart, lung, liver, and kidney.1,11,12
However, in vivo, IL-15 has been detected only in chronic
inflammatory diseases or autoimmune disorders. In synovial
tissues from rheumatoid arthritis (RA) patients and in alveolar macrophages of sarcoidosis patients, IL-15 has been identified by immuno-cytochemistry; in RA synovial fluids, high
levels of IL-15 (up to 1,200 ng/mL) have been detected by
ELISA techniques.13,14
Although monocytes and polymorphonuclear cells (PMN)
infiltrate the synovial cavities of RA patients, these cells
do not migrate in response to IL-15 in vitro.6 In addition,
subcutaneous injection of IL-15 in mice induces infiltration
From the Clinica Pediatrica, Universita’ di Brescia, Brescia; Dipartimento di Patologia e Medicina Sperimentale e Clinica, Universita’ di Udine, Udine; and from Dipartimento di Sanita’ Pubblica
e di Microbiologia, Universita’ di Torino, Torino, Italy.
Submitted February 10, 1997; accepted June 1, 1997.
Supported by a fellowship of ‘‘Comitato Promotore TeleThon,’’
Rome, Italy (to R.B). Partly supported by a grant from ‘‘First National Project on Tuberculosis, Istituto Superiore di Sanita,’’ Rome,
Italy; and by TeleThon, Rome, Italy, Grant A.42 (to L.D.N).
Address reprint requests to Tiziana Musso, PhD, Dipartimento di
Sanita’ Pubblica, Universita’ di Torino, Via Santena 9, 10126 Torino, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
q 1997 by The American Society of Hematology.
0006-4971/97/9007-0034$3.00/0
MATERIALS AND METHODS
Cell culture. Peripheral blood mononuclear cells (PBMC) were
obtained from normal volunteers who had provided informed consent. Monocytes were purified by Percoll gradient as described elsewhere.24 The purity of the monocyte preparations used in this study
was 90% { 4% as assessed by morphology on Giemsa-stained cytocentrifuge preparations and flow cytometry using the monocytespecific monoclonal antibody, LeuM3. PMN were purified essentially as described elsewhere.24 The preparations contained at least
95% PMN as judged by morphological criteria; the remaining cells
were mainly lymphocytes. Monocytes were cultured in RPMI 1640
(Advanced Biotechnology, Inc, Columbia, MD), containing 100 U/
mL penicillin, 100 mg/mL streptomycin, 2 mmol/L L-glutamine,
20 mmol/L HEPES (GIBCO, Grand Island, NY), and 10% heatinactivated fetal bovine serum (HyClone Lab, Logan, UT).
Cytokines. Human recombinant IL-15 was a kind gift of Dr
Tony Troutt (Immunex, Seattle, WA), IL-4, IL-8, and MCP-1 were
purchased from Peprotech (Rocky Hill, NJ). Human recombinant
interferon-g (IFN-g; lot NN9027AX, specific activity 2.02 1 107
U/mg) was kindly provided by Dr H.M. Shephard (Genentech Labs,
San Francisco, CA). All reagents and media, tested by the Endotoxin
kit (Sigma, St Louis, MO), contained endotoxin at levels lower than
12 pg/mL.
Northern blot analysis. For RNA extraction, 20 1 106 monoBlood, Vol 90, No 7 (October 1), 1997: pp 2804-2809
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IL-15 AND HUMAN MONOCYTES
2805
cytes were plated in 10 mL medium alone or supplemented with the
indicated cytokines. Total RNA isolation and Northern blot analysis
were performed as previously described.25 Briefly, 15 mg of total
RNA from each sample were electrophoresed under denaturing conditions, blotted onto Nytran membranes (Schleicher & Schuell Inc,
Keene, NH) and cross-linked by ultraviolet irradiation. Membranes
were prehybridized at 427C in Hybrisol (Oncor Inc, Gaithersburg,
MD) and hybridized overnight with 2 1 106 counts per minute (cpm)
of 32P-labeled probe. Membranes were then washed three times at
room temperature for 10 minutes in 0.21 sodium saline citrate (SSC)
0.1% sodium dodecyl sulfate before being autoradiographed using
Kodak XAR-5 films (Eastman Kodak, Rochester, NY) and intensifying screens at 807C. Probes were labeled by random priming reaction using a commercial kit (Boehringer Mannheim Biochemicals,
Indianapolis, IN) and a32P-deoxycytidine triphosphate (3,000 Ci/
mmol; Amersham, Arlington Heights, IL). The specific activity was
always higher than 109 cpm/mg. IL-8 and MCP-1 full-length cDNA,
kindly provided by Dr K. Matsushima (Kanazawa University Cancer
Institute, Kanazawa, Ishikawa-ken, Japan) were used.
Cytokine determination. IL-8, TNF-a, and IL-1b content of supernatants were determined by using commercial enzyme-linked immunosorbent assay (ELISA) kits obtained from Amersham while
MCP-1 concentration was assessed by an ELISA kit purchased from
R&D (Minneapolis, MN), following the manufacturer’s instructions
(sensitivity of assays: 3 pg/mL).
Migration assays. Monocyte-derived supernatants were diluted
1:2 with RPMI 1640 containing 1% bovine serum albumin (BSA),
and incubated at 377C for 20 minutes with irrelevant antibody (goat
IgG; Sigma), anti-IL-8 or anti-MCP-1 neutralizing antibodies (R&
D) at a concentration of 10 mg/mL, and assayed for chemotactic
activity for monocytes and PMN. Migration of monocytes and PMN
(1.5 1 106 cells/mL in RPMI 1640 / 1% BSA) was evaluated by
a microchamber technique as described elsewhere.24 For monocytes,
5-mm pore-size polycarbonate filters were employed. Under the assay
conditions employed, only monocytes in PBMC preparations migrated across the filter. Polyvinylpyrrolidone-free polycarbonate filters were used for PMN. At the end of the incubation (90 minutes
for monocytes and 30 minutes for PMN), filters were removed, fixed,
and stained by Diff-Quik (Harleco, Gibbstown, NJ), and three oil
immersion fields were counted after coding samples. In each assay,
N-formylmethionyl-leucyl-phenylalanine (fMLP; Sigma) at a concentration of 10 nmol/L was used as a standard chemoattractant for
monocytes or PMN. Statistical analysis of the results was performed
by using analysis of variance (ANOVA) test for repeated measures.
RESULTS
To assess whether IL-15 might induce chemokine production in monocytes, cells were stimulated with IL-15 at concentrations up to 1,000 ng/mL. After 24 hours of incubation,
supernatants derived from the culture were examined for
PMN and monocyte chemotactic activity. IL-15–stimulated
monocytes released chemoattractants for both monocytes
and PMN into supernatants; in contrast, boiled-IL-15 failed
to induce secretion of chemotactic factors (data not shown).
To identify which chemokines were produced by IL-15–
stimulated monocytes, we used neutralizing antibodies
against IL-8 and MCP-1, two chemokines produced in large
amounts by monocytes stimulated with other cytokines, such
as IL-1, TNF, or LIF16-18. Anti-IL-8 antibodies neutralized
up to 65% of the PMN chemotactic activity in supernatants
derived from IL-15–stimulated monocytes, while IgG, used
as control, did not affect PMN chemotaxis in response to
the same supernatants (Fig 1A). Monocyte chemotactic activity of supernatants from IL-15 stimulated monocyte was
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Fig 1. Chemotactic activity of supernatants derived from monocytes stimulated with IL-15 for PMN (A) or monocytes (B). (j) Supernatants treated with control IgG. ( ) Supernatants treated with antiIL-8 or anti-MCP-1 neutralizing antibodies. Results represent mean
Ô SE of three independent experiments. *Significant chemotactic
response in comparison to medium (P Ú .05). †Significant inhibition
by treatment with neutralizing antibodies in comparison to treatment with control IgG (P Ú .05).
reduced up to 90% by preincubation with anti-MCP-1 antibodies; normal IgG did not change monocyte response to
the medium (Fig 1B).
Experiments were performed to determine whether the
production of IL-8 and MCP-1 in monocytes stimulated by
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2806
BADOLATO ET AL
Table 1. Production of IL-8 by Human Monocytes
Upon Stimulation by IL-15
IL-8 (ng/mL) Mean (SD)
Treatment*
Medium
IL-15 (10 ng/mL)
(100 ng/mL)
(1,000 ng/mL)
6h
14
25
34†
141†
(3.3)
(1.8)
(2.6)
(6.4)
24 h
27
42
70†
176†
(4.1)
(3.4)
(6.2)
(8.7)
* Supernatants derived from monocytes cultured with increasing
concentrations of IL-15 (from 10 to 1,000 ng/mL), or medium alone
for 6 or 24 hours were analyzed in duplicate for their concentration
of IL-8 by ELISA. Results shown are representative of a single experiment out of three performed.
† Significant production in comparison to medium (P õ .05).
Fig 2. Northern blot analysis of the expression of IL-8 in the presence of increasing concentrations of IL-15. Monocytes were incubated for 4 hours in medium alone or supplemented with IL-15. Lower
panel shows ethidium-bromide staining of total RNA.
IL-l5 was associated with an increased expression of mRNA
for these chemokines. Total RNA was obtained from monocytes treated with increasing concentrations of IL-15 for 6
hours. Figure 2 shows that a low basal level of IL-8 mRNA
was detected in untreated monocytes. IL-15 caused a dose
dependent increase of IL-8 mRNA. Time course experiments
indicated that IL-8 mRNA expression was observed as early
as 1 hour after stimulation and was maximal after 6 hours
(data not shown). Induction of MCP-1 mRNA was also detected after IL-15 stimulation; however, the peak of MCP1 mRNA expression was reached 18 hours after stimulation.
Donor to donor variation was obtained in the constitutive
expression of IL-8 and MCP-1 mRNA expression in unstimulated cells; however, in 6 out of 6 donors, an increased
expression of IL-8 and MCP-1 mRNA was consistently observed after treatment with IL-15.
To confirm that the induction of IL-8 and MCP-1 mRNA
was associated with protein secretion, supernatants from
monocytes were harvested at various times after stimulation
with IL-l5, and IL-8 and MCP-1 protein levels were quantitated by ELISA. As shown in Table 1, IL-8 production by
monocytes was increased by stimulation with IL-15 at concentrations as low as 100 ng/mL, as early as 6 hours. After
24 hours of stimulation, the production of IL-8 reached its
maximal level. No further increase could be detected at subsequent time points (data not shown). MCP-1 was detectable
6 hours after stimulation of the cells with 100 ng/mL of IL15, but decreased with time (Table 2). The lack of accumula-
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tion of MCP-1 in the culture medium might be caused by
increased utilization and degradation of the chemokine via
MCP-1 receptors expressed on monocytes. Significant
amounts of both IL-8 and MCP-1 were consistently detected
in supernatants derived from monocytes stimulated with IL15 at concentrations of 100 ng/mL in three out of three
subjects studied (P õ .05).
Antigen-dependent activation of T cells induces proliferation but also cytokine-production; IL-2, IL-4, and IFN-g,
secreted by T cells, can also regulate many monocyte functions including the production of chemokines.26 IFN-g is
known to stimulate cytotoxic and antibacterial activities of
monocytes, but also to inhibit IL-8 expression and to induce
MCP-1 and IP-10 secretion.18,27,28 When monocytes were
incubated for 6 hours with IL-15 and IFN-g, we observed
that IL-8 release in the supernatants was reduced almost to
the basal level (Fig 3). IFN-g alone was about 10 times more
potent than IL-15 for the induction of MCP-1, but when the
two cytokines were used together, a synergistic upregulation
of MCP-1 production was observed (Fig 4). IL-4 may display
both stimulatory and inhibitory effects on monocytes: it induces CD23 expression,29 but inhibits IL-1b and TNF-a
production by LPS-activated monocytes.30,31 We found that
IL-4, used at concentrations of 100 U/mL, is a potent inhibitor of IL-8 and MCP-1 production by human monocytes
stimulated with IL-15 (Figs 3 and 4).
Table 2. Production of MCP-1 by Human Monocytes
Upon Stimulation by IL-15
MCP-1 (ng/mL)
Mean (SD)
Treatment*
Medium
IL-15 (10 ng/mL)
(100 ng/mL)
(1,000 ng/mL)
6h
0.16
0.44
0.78†
1.85†
(0.1)
(0.2)
(0.16)
(0.31)
24 h
õ0.014
0.05
0.14
1.03†
(0.01)
(0.09)
(0.12)
(0.2)
* Supernatants derived from monocytes cultured with increasing
concentrations of IL-15 (from 10 to 1,000 ng/mL), or medium alone
for 6 or 24 hours were analyzed in duplicate for their concentration
of MCP-1 by ELISA. Results shown are representative of a single experiment out of three performed.
† Significant production in comparison to medium (P õ .05).
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IL-15 AND HUMAN MONOCYTES
2807
Fig 3. Regulation by IL-4 and IFN-g of IL-8 production in IL-15–
stimulated monocytes. Monocytes were incubated with medium
alone or supplemented with IL-15 (1,000 ng/m), IL-4 (100 U/mL), IFNg (500 U/mL), IL-15 plus IL-4, or IL-15 plus IFN-g. After 6 hours supernatants were assayed for IL-8 content by ELISA. Results represent
mean Ô SE of IL-8 concentrations of three independent experiments.
*Significant difference of IL-8 concentration (P Ú .05). †Significant
inhibition by treatment (P Ú .05).
DISCUSSION
We have shown that IL-15, in addition to its effect on T
cells, also exhibits effects on monocytes, and may act as a
proinflammatory cytokine inducing monocytes to secrete
both PMN and monocyte chemotactic factors. IL-8 and
MCP-1 are chemokines identified in supernatants derived
from IL-15–stimulated monocytes as shown by experiments
of neutralization of chemotactic activities of supernatants
with anti-IL-8 or anti-MCP-1 as well as with immunoenzymatic assays (Figs 1 and 2, Tables 1 and 2). IL-8 and MCP1, as well as IL-15, are also present in inflamed joints of
rheumatoid arthritis patients,13,21,32 suggesting that IL-15
stimulation of synovial macrophages might contribute to the
induction of IL-8 and MCP-1 production in synovial fluids.
High concentrations of the two chemokines are detected
within 6 hours of stimulation of monocytes with IL-15 at
concentrations as low as 100 ng/mL (Tables 1 and 2). Activated monocytes may secrete other cytokines such as IL-1a
and b, and TNF-a, that in turn can induce production of IL8 and MCP-1.16,18 Thus, IL-15 induction of chemokines
might be mediated through release of these proinflammatory
cytokines. However, monocyte supernatants assayed for IL1b, and TNF-a content by ELISA, showed that IL-15 at
concentrations of 10 or 100 ng/mL failed to induce detectable
amounts of IL-1b, and TNF-a (data not shown), as previously reported by McInnes et al.33 Instead, we saw that
higher concentrations of IL-15 (1,000 ng/mL), consistently
induced secretion of both IL-1b and TNF-a (data not
shown). As a whole, our results indicate that IL-15, at concentrations up to 100 ng/mL, may directly induce IL-8 and
MCP-1 at both mRNA and protein level without involving
TNF-a or IL-1b; but higher concentrations of IL-15 (1,000
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ng/mL) also induce a concomitant release of TNF-a, and
IL-1b that may enhance the level of chemokine production.
IL-15, originally identified for its T-cell proliferative activity in supernatants derived from a monkey-kidney epithelial cell line (CVI/EBNA) and from a human adult T-cell
leukemia cell line (HuT-102), is expressed at the mRNA
level ubiquitously in organs and tissues.1,2 Although IL-15
mRNA is induced in vitro on a variety of stimuli, IL-15
protein is usually not detectable in supernatants, probably
because its secretion is tightly regulated at a posttranslational
level.12,34 However, IL-15 protein is secreted in large
amounts in synovial fluid derived from RA patients (up to
1,200 ng/m), and expressed in macrophages derived from
patients affected by pulmonary sarcoidosis, and in fibroblasts
and keratinocytes of normal skin, suggesting that IL-15 protein may be secreted in vivo during inflammatory responses.13,14 We found that production of IL-8 and MCP-1
is induced by IL-15 at concentrations (100 ng/m) that are
reached in pathological conditions such as RA, that are characterized by an important inflammatory response. In these
diseases, IL-15 may contribute to leukocyte recruitment to
tissues not only by direct chemotaxis of T cells, but also
by induction of other chemoattractants such as IL-8 and
MCP-1.
T cells recruited to the site of inflammation, if activated
by T-cell receptor triggering may differentiate into a Th1
or Th2 phenotype, depending on the pattern of cytokine
production. Secretion of IFN-g will activate leukocyte cytotoxicity, while predominance of IL-4 will divert the immune
system to mount an antibody-mediated response. IL-4 is
known to act on monocytes through the common chain pathway exerting both activating or inhibiting effects. However,
in monocytes IL-4 is a potent inhibitor of cytokine release
induced by bacterial components or by proinflammatory cy-
Fig 4. Regulation by IL-4 and IFN-g of MCP-1 production by IL-15–
stimulated monocytes. Monocytes were incubated under the conditions described in the Fig 3 legend. After 6 hours supernatants were
assayed for IL-8 content by ELISA. Results represent mean Ô SE of
MCP-1 concentrations of three independent experiments. *Significant difference of MCP-1 concentrations (P Ú .05). †Significant inhibition by treatment (P õ .05).
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2808
BADOLATO ET AL
tokines.30,35 We observed that IL-4 prevents IL-15 induction
of the chemokines IL-8 and MCP-1 in human monocytes.
The effect of IL-4 was obtained at concentrations as low as
100 U/mL and could not be overcome by increasing IL-15
concentrations up to 1,000 ng/mL (data not shown).
In contrast to IL-4, IFN-g activates many functions of
monocytes including antibacterial activity, cytotoxicity, and
cytokine production.26 We observed that production of IL-8
and MCP-1 induced by IL-15 can be modulated by IFN-g.
IL-8 secretion by IL-15–stimulated monocytes is inhibited
upon treatment with IFN-g. Conversely, MCP-1 secretion,
induced by IL-15, is strongly synergized by IFN-g. We speculate that Th1 and/or Th2 cytokines produced by T cells
may fine-tune chemokine expression in monocytes upon IL15 stimulation in vivo. IL-4, preventing IL-8 and MCP-1
production, will exert anti-inflammatory properties by reduction of PMN and monocyte infiltration in inflamed tissue.
Secretion of IFN-g may act in vivo as a switch that, by
differentially regulating IL-8 and MCP-1 production, diverts
the leukocyte infiltrate from neutrophilic to monocytic.
The inhibitory effect of IFN-g on IL-8 expression was
previously observed in monocytes stimulated with IL-1, IL2, or LIF18,27; IFN-g inhibits transcriptional activation of IL8 gene by decreasing NF-kB transactivating activity.36 It is
unclear, however, how IFN-g might enhance IL-15–induced
secretion of MCP-1. We have previously reported that IFNg does not affect LIF-induced production of MCP-1,18 indicating that the combined effect of IL-15 and IFN-g might
involve other mechanisms such as the upregulation of IL15–receptor expression or of other components involved in
the signaling pathways of these two cytokines. Monocytes,
constitutively express IL-2Rb chain, the common g chain,
and the tyrosine kinase Jak-3 that mediates, in other cell
types, the signaling response to IL-15.37-40 It has been reported that IFN-g upregulates the expression of these IL15–receptor subunits, suggesting a possible mechanism for
the observed synergism between IL-15 and IFN-g.37-39 Nevertheless, the signaling pathway of IL-15 in human monocytes has not been defined. It is unclear whether unstimulated
monocytes express IL-15R a chain or other IL-15–receptor
subunits identified on mast-cells. Although lacking the IL2R g chain, mast-cells still bind IL-15, and upon stimulation
with the cytokine, tyrosine-phosphorylation of Jak-2 but not
of Jak-3 and Jak-1 was observed.34,41 We are currently studying the expression and regulation of IL-15 receptor a chain
in monocytes to characterize the signaling pathway of IL15 in these cells and to clarify whether the effects of IL-15
described in this study might be mediated through these
additional IL-15 receptor subunits.
ACKNOWLEDGMENT
The authors thank Drs Ji Ming Wang and Michael Grimm for
kindly reviewing the manuscript, and Dr Antonio Sica for helpful
suggestions.
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bldal
WBS: Blood
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
1997 90: 2804-2809
Interleukin-15 (IL-15) Induces IL-8 and Monocyte Chemotactic Protein 1
Production in Human Monocytes
Raffaele Badolato, Alessandro Negro Ponzi, Maura Millesimo, Luigi D. Notarangelo and Tiziana Musso
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