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HEMATOPOIESIS
From the Biochemistry II group, Research Department,
Sawai Pharmaceutical, Osaka, Japan; and the Laboratory of Host
Defenses, Institute for Advanced Medical Sciences and the Department of
Emergency and Disaster Medicine, Hyogo College of Medicine, Hyogo,
Japan.
Because interleukin-18 (IL-18) is similar to IL-1 and is known to
be involved in the hematopoietic progenitor cell growth, the effect of
IL-18 on circulating cell populations was examined. Repeated
administration of IL-18 induced significant amounts of neutrophilia in
mice. In parallel, high levels of interferon- Dramatic changes in hematologic profiles can
occur during inflammatory responses induced by various kinds of
insults. Leukocyte profiles in the blood are often altered in
conjunction with physiologic changes. Various mediators, cytokines, and
growth factors, are involved in these changes. Interleukin-1 (IL-1) has
been shown to be responsible for neutrophilia as well as fever. IL-18,
originally discovered as a gamma interferon-inducing
factor,1 shares many features with IL-1, including the
molecular structure, processing, and signaling pathway through NF- Animals
Preparation of CD4+ T, CD8+ T, and B cells
by magnetic cell separation
Cell cultures Cells were suspended in RPMI 1640 medium supplemented with 10% FCS, 10 mM glutamine and 2 × 10-5M 2-mercaptoethanol, and plated on 6-well or 24-well culture dishes at a cell density of 2 × 107 or 5 × 106/mL, and cultured for appropriate lengths of time.Analysis of cells by FACs Cells were pretreated with the antibody-blocking Fc receptor, CD16/32 (BD-Pharmingen) to inhibit nonspecific antibody binding, and were incubated with a combination of fluorescein isothiocyanate (FITC)-conjugated antimouse CD4 (L3T4; BD-Pharmingen), phycoerythrin (PE)-conjugated antimouse CD45R/B220 (RA3-6B2; BD-Pharmingen) and CyChrome-conjugated antimouse CD8 (Ly-2; BD-Pharmingen) antibodies for 30 minutes at 4°C. Cells were washed 3 times with staining buffer composed of PBS supplemented with 2% FCS and 0.05% NaN3 and analyzed by FACs Caliber (Becton Dickinson).Analysis of mRNA by reverse transcriptase-polymerase chain reaction RNA was extracted from cell pellets using Isogen extraction buffer according to the manufacturer's manuals (Nippon Gene, Tokyo, Japan). Precipitated RNA was dissolved in RNase-free water and the concentrations were spectrophotometrically determined. DNA was synthesized using random hexamer primers and amplified by GeneAmp PCR system 9700 (PerkinElmer, Foster City, CA). Sequences of primers used were as follows: 5'-CGTGACAAGCAGAGATGTTG-3' for murine IL-18R sense, 5'-ATGTTGTCGTCTCCTTCCTG-3' for murine IL-18R antisense, 5'-ATGCTCTGTTTGGGCTGGGT-3' for murine IL-18R sense, 5'-CTGTCTTGATACAACAGGCCA-3' for murine IL-18R antisense,
5'-ATGGCTCAACTTTCTGCCCA-3' for murine G-CSF sense and
5'-AATACCCGATAGAGCCTGCA-3' for murine G-CSF antisense,
5'-CTGCAGGAGTGTCCATCACGGTGAAAGA-3' for murine Fc- receptor I sense,
5'-GGATGTGAAACCAGACAGGAGCTGATGA-3' for murine Fc- receptor I
antisense and 5'-CCATCACCATCTTCCAGGAGCGAG-3' for murine glyceraldehyde
phosphate dehydrogenase (GAPDH) sense, 5'-CACAGTCTTCTGGGTGGCAGTGAT-3' for murine GAPDH antisense. Polymerase chain reaction (PCR) amplification was performed using 35 cycles of
primer extension at 72°C for 1 minute, annealing at 58°C for 30 seconds and denaturating at 94°C for 30 seconds. Products were visualized by 1.5% agarose-gel electrophoresis followed by ethidium bromide staining.
Enzyme-linked immunosorbent assay Enzyme-linked immunosorbent assay (ELISA) systems for IL-3, IL-5, IL-6, GM-CSF, and IFN- were purchased from BD-Pharmingen. Other reagents necessary for ELISA were purchased from Sigma Chemical (St Louis, MO). The assays were carried out according to the
manufacturer's manuals, using substrate solution of
3,3',5,5'-tetramethylbenzidine (TMB) (Sigma T-8540;
Sigma Chemical). OD values at 450 nm were measured by a
microplate reader system (Bio-rad, Hercules, CA), and the
concentrations were calculated using the computer program MPM
III (Bio-rad).
Treatment of mice with IL-18 and measurement of blood cell counts Recombinant mouse IL-18 (2 µg, 0.6 µg, and 0.2 µg in 0.2 mL PBS) or PBS was injected into 16 mice subcutaneously daily for 5 weeks. On every seventh day, blood was collected by tail cut. Blood samples (5 µL) were treated with Turk solution at 4°C to eliminate red blood cells, and the cell suspensions were plated on a slide glass by CytoSpin and stained with Diff-Quick (Midori, Osaka, Japan). White blood cells were counted under microscope.Measurement of serum cytokine levels before and after treatment with IL-18 Forty-eight mice were treated with IL-18 or PBS as described above, killed on every seventh day, and the blood samples were collected for the determination of serum cytokines using ELISA systems.
Induction of neutrophilia and eosinophilia by repetitive administration of IL-18 in mice Daily subcutaneous administration of IL-18 at a dose of 2 µg/mouse significantly increased neutrophil counts in circulation from 2 weeks after the beginning of administration (Figure 1A). Elevated neutrophil counts were maintained while IL-18 was administered, but counts reversed to the basal level within 1 week after withdrawal of administration of IL-18. The eosinophil number in circulation also increased during 3 to 5 weeks of IL-18 treatment (Figure 1B). This elevation was also reversed to the basal level within 1 week of withdrawal of IL-18. Total white blood cell counts did not change significantly during cytokine treatment (Figure 1C). Levels of lymphocytes were significantly reduced during IL-18 treatment, but were returned to the basal level within 1 week of withdrawal of IL-18 (Figure 1D).
Administration of lower concentrations of IL-18 (0.2 µg/mouse and 0.6 µg/mouse) caused only small increases in the number of neutrophils
and eosinophils (Table 1). At 2 µg/mouse, significant increases in the number of these cells
were observed. The average serum concentrations of IL-18 during
administration were 201.61 ± 14.84, 79.72 ± 3.95, and
22.47 ± 3.10 ng/mL for mice that received 2 µg, 0.6 µg, and 0.2 µg of IL-18, respectively (Table 1).
Elevation of serum cytokine levels in mice treated with IL-18 Based on the results shown in Table 1, we tested the effect of 2 µg/mouse IL-18 on serum cytokine levels in mice. Daily subcutaneous injection with IL-18 at this dose induced significant amounts of GM-CSF and IL-5 in sera 2 to 5 weeks after the first administration (Figure 2A,B). Serum IL-6 levels were elevated 1 week after the IL-18 treatment, reached a peak at 2 weeks, and then rapidly decreased (Figure 2C). Similar transient elevation was observed with IFN- (Figure 2D). On the other hand, daily administration of
IL-18 failed to induce IL-3 and IL-1 in the sera of mice (data
not shown).
Effect of IL-18 on circulating blood cells in
IFN- -deficient mice caused significant increases in the number of neutrophils, although the major elevation occurred 3 weeks after the
beginning of the IL-18 administration (Figure
3A), as compared with 2 weeks with the
healthy mice. The number of eosinophils started to increase at 1 week
(Figure 3B), much earlier than observed with the healthy mice (3 weeks); remained high for an additional 4 weeks; and returned to the
basal level within 1 week of withdrawal of IL-18 (Figure 3B). Total
white blood cell count did not change significantly during cytokine
treatment (Figure 3C). Levels of lymphocytes were significantly reduced
3 weeks after the beginning of administration of IL-18, but were
returned to the basal level within 1 week of withdrawal of IL-18
(Figure 3D).
Induction of hematopoietic cytokine secretion by IL-18 in vitro Treatment of splenocytes with IL-18 for 72 hours stimulated secretion of GM-CSF, IL-5, IL-6, and IFN- in a
concentration-dependent manner (Figure
4). IL-12 failed to stimulate secretion
of these cytokines (data not shown), but it enhanced the effect of
IL-18 to induce GM-CSF, IL-6 (Figure 4A,C  ) and, in particular,
IFN- (Figure 4D ). IL-5 secretion induced by IL-18, on the other
hand, was almost completely repressed by IL-12 (Figure 4B ). IL-18 induced negligible amounts of IL-3 both in the presence and absence of
IL-12 (data not shown). We investigated the effect of IFN- on
the cytokine secretion stimulated by IL-18 using the splenocytes isolated from IFN--deficient mice (Figure 4). GM-CSF
secretion was found to be enhanced by IL-18 (Figure 4A [bottom]).
Enhanced IL-5 secretion induced by IL-18 and its inhibition by IL-12
were not affected by the IFN- deficiency (Figure 4B [bottom]). In contrast to wild-type splenocytes, however, IL-6 secretion induced by
IL-18 was only slightly enhanced in IFN--deficient splenocytes (Figure 4C [bottom]).
Expression of G-CSF mRNA in splenic adherent cells treated with IL-18 Because there are no ELISA kits available for detecting mouse G-CSF, we performed RT-PCR for murine G-CSF mRNA to determine the effect of IL-18 on G-CSF expression. As shown in Figure 5, IL-18 was found to induce G-CSF mRNA expression in splenic adherent cells.
Identification of cells expressing IL-18 receptor mRNA The expression of IL-18 receptors was analyzed in CD4+ and CD8+ T cells and CD43 B cells prepared by
MACs. Purity of CD4+ T cells, CD8+ T
cells, and B cells, checked by the flow-cytometric analysis, were
96.8%, 96.6%, and 99.2%, respectively (Figure
6A). Messenger RNAs for IL-18R and
IL-18R (AcPL) were detected in CD4+ and CD8+
T cells and splenic adherent cells, but not in B cells (Figure 6B).
This indicates that the expression of IL-18 receptors on these cells
does not require stimulation by IL-18. Fcry receptor type I (Fc-
RI) mRNA, the marker of NK cells and macrophages, was detected
only in splenic adherent cells (Figure 6B).
Identification of cells secreting cytokines in response to IL-18 in vitro CD4+ and CD8+ T cells, B cells, and splenic adherent cells were cultured in the presence of IL-18, IL-12, or both for 72 hours, and several cytokines in culture supernatant were analyzed by ELISA systems (Figure 7). We found that CD4+ T cells stimulated by IL-18 secreted large amounts of GM-CSF, IL-5, and IL-3 (Figure 7A-C), whereas these cytokines were hardly detectable in the supernatant of CD8+ T cells (Figure 7E-G). In CD4+ cells, IL-12 stimulated secretion of GM-CSF and IL-3 but inhibited IL-5 secretion (Figure 7A-C). IL-6 was secreted by splenic adherent cells incubated with IL-18, which was further enhanced in the presence of IL-12 (Figure 7P). Low levels of IL-6 secretion were also observed from CD4+ T cells stimulated by IL-18 and IL-12 (Figure 7D). No IL-6 was detected in the supernatant of CD8+ T cells stimulated by IL-18 and IL-12 (Figure 7H). B cells did not secrete any of the cytokines analyzed with or without treatment with IL-18 and IL-12 (Figure 7I-L).
In the present study, we observed that continuous administration
of IL-18 caused significant neutrophilia and lymphopenia with
subsequent weak eosinophilia in mice (Figure 1). It also induced
secretion of various cytokines into circulation, which changed parallel
to the change in leukocyte populations (Figure 1 and Figure 2). In the
first 2 weeks of IL-18 administration, when the number of neutrophils
was elevated and that of lymphocytes was reduced, IFN- These observations are interesting because IL-18 has been shown to
induce production of cytokines of both Th1 type (IFN- It has been observed that IL-18 is expressed in the lesions or secreted in the circulation of various diseases including autoimmune diseases, GVHD, purine nucleoside phosphorylase (PNP) deficiency, and lepromatous leprosy.10,11,15,28 However, the pathologic significance of these observations remains obscure because this cytokine seems to be involved in both destructive and compensatory pathways in inflammatory diseases. Clarification of pathophysiologic roles of IL-18 may be of value for understanding the cause and/or symptoms of various diseases. In the present experiments, we demonstrated that IL-18 augmented the
expression of hematopoietic cytokines and growth factors, such as IL-3,
IL-5, IL-6, GM-CSF, and G-CSF (Figures 2, 4, and 5). All these
cytokines except IL-6 have been suggested to be derived from
CD4+ T cells or macrophages (Figure 7). Our in vitro
experiments showed that splenic adherent cells but not CD4+
and CD8+ cells secreted IL-6, suggesting that this cytokine
was secreted mostly by macrophages (Figure 7). We found that IL-18
receptors were constitutively expressed on T cells (both CD4 and CD8)
and splenic macrophages (Figure 5). The receptor for IL-18 is composed of inducible IL-18R It is well known that G-CSF, GM-CSF, and IL-3 regulate the development and activation of neutrophils and promote their proliferation and survival.32,36 IL-6 also may play a role in hematopoiesis because it has been shown that Escherichia coli is unable to efficiently induce neutrophilia in IL-6-deficient mice, and antibodies to GM-CSF and IL-6 abrogate the augmentation of survival of neutrophils cultured in the supernatant of epithelial cells.37,38 In our experiments discussed here, daily administration of IL-18 resulted in induction of these cytokines in mice. It is therefore possible that the progressive neutrophilia caused by IL-18 may result from the induction of cytokines, such as IL-3, and growth factors, such as G-CSF and GM-CSF. Lauwerys et al have shown that splenocytes stimulated by a combination
of IL-12 and IL-18 produce IFN- It is widely accepted that the hematopoietic growth factors, IL-3,
IL-5, and GM-CSF, regulate the survival, maturation, and activation of
eosinophils.40 It has also been demonstrated that spontaneous decreases in viability of rat peritoneal eosinophils are
inhibited by recombinant IL-541 and that blockade of IL-5 results in inhibition of eosinophil accumulation in an experimental model for airway inflammation.42 Because there was a lag
in the appearance of neutrophilia and eosinophilia induced by the daily
administration of IL-18 which was coincident with the change in
circulating cytokines from IFN- Proliferation, differentiation, and maturation of hematopoietic cells are regulated by a variety of cytokines and growth factors, such as IL-3, IL-5, GM-CSF, G-CSF, stem cell factor, and IL-6. In this study, we demonstrated that IL-18 induced IL-5, IL-6, GM-CSF, and G-CSF. The recruitment and activation of polymorphonuclear leukocytes is the hallmark of acute inflammation. Especially, neutrophils are the most abundant cells in the blood and are essential for host defenses and for inflammatory responses. Eosinophils are present only in a trace number in the healthy blood, but increase in number in case of infection and allergy. The primary use of colony-stimulating factors in patients receiving chemotherapy is to reduce the incidence of febrile neutropenia, leading to the reduction of use of antibiotics and hospitalization time.43-45 The fact that IL-18 increases circulating neutrophils may also suggest that it may have beneficial effects on the neutropenia during anticancer chemotherapy and agranulocytosis. On the other hand, IL-18 elevates the number of eosinophils mediating atopic dermatitis, asthma, and allergy, and thus acts as a worsening factor. In this case, IL-18 should be used as a target for neutralization in the strategy for the control of such diseases.
The authors thank Dr T. Tamaoki for important suggestions and critical reading of the manuscript.
Submitted December 8, 2000; accepted May 25, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Haruki Okamura, Laboratory of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan; e-mail: haruoka{at}hyo-med.ac.jp.
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© 2001 by The American Society of Hematology.
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 K. Hosohara, H. Ueda, S.-I. Kashiwamura, T. Yano, T. Ogura, S. Marukawa, and H. Okamura Interleukin-18 Induces Acute Biphasic Reduction in the Levels of Circulating Leukocytes in Mice Clin. Vaccine Immunol., July 1, 2002; 9(4): 777 - 783. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
B.
Both IL-1 and IL-18 are synthesized as inactive precursor forms which
are processed by IL-1
