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Division of Arthritis Research, The Scripps Research Institute, La Jolla, CA 92037
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducing factor,
is a member of the IL-1 family of proteins. Because IL-1
and IL-1ß
are important mediators in the pathogenesis of arthritis, the present
study addresses the expression of IL-18 and its role in regulating in
articular chondrocytes. IL-18 mRNA was induced by IL-1ß in
chondrocytes. Chondrocytes produced the IL-18 precursor and in response
to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18
effects on chondrocytes showed that it inhibits TGF-ß-induced
proliferation and enhances nitric oxide production. IL-18 stimulated
the expression of several genes in normal human articular chondrocytes
including inducible nitric oxide synthase, inducible cyclooxygenase,
IL-6, and stromelysin. Gene expression was associated with the
synthesis of the corresponding proteins. Treatment of normal human
articular cartilage with IL-18 increased the release of
glycosaminoglycans. These finding identify IL-18 as a cytokine that
regulates chondrocyte responses and contributes to cartilage
degradation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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are principal mediators in the pathogenesis of arthritis (1).
Neutralization of TNF- is a promising intervention in human
rheumatoid arthritis (2), and intra-articular expression of IL-1ß in
rabbits can produce the major pathologies of human rheumatoid arthritis
(3).
In chondrocytes two qualitatively distinct functional programs can be
distinguished. The catabolic program is induced by proinflammatory
stimuli and characterized by the secretion of proteases, suppression of
matrix synthesis, and inhibition of chondrocyte proliferation. The
anabolic program is associated with the production of extracellular
matrix, protease inhibitors, and cell replication. IL-1 is the
prototypic inducer of catabolic responses in chondrocytes (4). IL-1
stimulates the expression of proteases including stromelysin,
collagenase (5, 6), and tissue plasminogen activator (7). IL-1
suppresses 1 (II) procollagen mRNA expression (8) and type II
collagen and proteoglycan synthesis (9). IL-1 is also a potent inducer
of PG synthesis, and this is related to the induction of cyclooxygenase
II (COXII)3 gene expression
(10). Nitric oxide (NO) production is part of the catabolic program in
chondrocytes. Inducible nitric oxide synthase (iNOS) is induced by IL-1
or TNF (11), but not by the growth factors TGF-ß, platelet-derived
growth factor, or insulin-like growth factor (12). The IL-1 inhibition
of proteoglycan synthesis (9) and of chondrocyte proliferation (13)
depends at least in part on endogenous NO. Exogenous NO donors can also
induce apoptosis in chondrocytes (14, 15).
The formation of cartilage extracellular matrix is primarily stimulated by growth factors such as TGF-ß, insulin-like growth factor, and fibroblast growth factor (16, 17). IL-1 suppresses many of the anabolic effects of these growth factors (18, 19).
In synoviocytes, IL-1 induces a similar spectrum of genes as in chondrocytes, and this includes a large number of cytokines, metalloproteinases, and adhesion molecules. In contrast with chondrocytes, IL-1 stimulates the proliferation of synoviocytes and may contribute to pannus formation (20).
IL-18 is a cytokine that was originally identified as IFN--inducing
factor. IL-18 has structural similarities with the IL-1 family of
proteins (21). IL-18 is also synthesized as a biologically inactive
precursor and cleaved by the IL-1 converting enzyme (ICE, or also
termed caspase I) (22, 23). IL-18 gene expression has been demonstrated
in murine macrophages, Kupffer cells (21), osteoblasts (24), and in the
adrenal cortex (25). The human IL-18 cDNA was isolated from a liver
cDNA library. Human rIL-18 induced IFN- production by
mitogen-stimulated PBMC, augmented granulocyte-macrophage CSF
production, and inhibited IL-10 production (26). IL-18 also stimulated
the proliferation of activated T cells and inhibited the formation of
osteoclast-like cells (24). The human IL-18R was purified (27), and its
sequence was found to be identical to the previously known
IL-1R-related protein (28).
In view of the structural homology with IL-1, the present study examined whether joint tissue cells express IL-18 and determined IL-18 effects on connective tissue metabolism. The results show that IL-18 can be produced by chondrocytes and activates responses in chondrocytes that contribute to the pathogenesis of arthritis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cartilage from the femoral condyles and tibial plateaus of the knee joints was obtained at autopsy from donors without known history of joint disease or from healthy organ donors from the University of California at San Diego tissue bank. Cartilage slices were cut into pieces (2–3 mm3), washed with DMEM (BioWhittaker, Walkerville, MD), and treated for 15 min with trypsin (10% (v/v)) in a 37°C waterbath. The tissues were transferred to DMEM, 5% FBS, penicillin-streptomycin-fungizone, and 2 mg/ml clostridial collagenase type IV (Sigma, St. Louis, MO) and digested overnight on a gyratory shaker. The cells were washed three times with DMEM and cultured in DMEM and 5% FBS.
Chondrocyte proliferation studies
All experiments were performed with chondrocytes in primary culture. Cells were distributed into 96-well plates (5000/well) in a total volume of 100 or 200 µl of DMEM supplemented with L-glutamine, penicillin, streptomycin, and dialyzed FBS as indicated in each experiment with the various stimuli in triplicate. After 3–5 days, the cultures were pulsed with [3H]TdR (1 µCi/well) for 12 h and the cells were harvested on glass fiber filter paper by a multiwell automated-PHD cell harvester. Total radioactivity was quantified by liquid scintillation counting.
RNA isolation and RT-PCR
Total RNA was isolated by a single step guanidinium thiocyanate-phenol-chloroform method. Cells were lysed directly in the flasks using RNA Stat60 (Tel-Test, Friendswood, TX), and the samples were processed following the manufacturer’s protocol.
cDNA was prepared from RNA using random hexamers and SuperscriptII (Life Technologies, Gaithersburg, MD) according to the manufacturer’s suggestion. PCR was performed with the following primers: IL-18, 5'-GCT TGA ATC TAA ATT ATC AGT C-3' and 5'-GAA GAT TCA AAT TGC ATC TTA T-3' (26); IL-6, 5'-CAC AGA CAG CCA CTC ACC TCT TC-3' and 5'-GCT GCG CAG AAT GAG ATG AGT TGT-3'; stromelysin, 5'-TGG ACA AAG GAT ACA ACA GGG A-3' and 5'-AGC TCG TAC CTC ATT TCC TCT G-3'; COXII, 5'-TTG TCC CAG ACA AGC AGG C-3' and 5'-CAT TCC TAC CAC CAG CAA CC-3'; iNOS, 5'-ACA TTG ATC AGA AGC TGT CCC AC-3' and 5'-CAA AGG CTG TGA GTC CTG CAC-3'; and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), 5'-TGG TAT CGT GGA AGG ACT CAT GAC-3' and 5'-ATG CCA GTG AGC TTC CCG TTC AGC-3'.
Quantification of nitrites
Chondrocytes were plated at 50,000 cells per well in 96-well plates and cultured for 48 h when culture supernatants were collected for nitrite measurements.
NO formation was detected by NO2- accumulation in the culture supernatants by the Griess reaction, using sodium nitrite as standard. Briefly, 50 µl of culture supernatant were incubated with 50 µl 1% sulfanilamide and 0.1% N-1-naphthylethylenediamide dihydrochloride in 25% H3PO4 at room temperature for 5 min. Optical density was measured at 570 nm.
IL-6 ELISA
Half-area ELISA plates (Costar, Cambridge, MA) were coated with 25 µl of 2 µg/ml monoclonal mouse anti-human IL-6 Ab (R&D Systems, Minneapolis, MN) for 3 h and blocked with 3% BSA. Twenty-five microliters of samples or human IL-6 standard were added to the plate and incubated for 2 h followed by 1 µg/ml rabbit anti-human IL-6 (R&D Systems). Biotin-labeled goat anti-rabbit Ig (Sigma) was then added (1:2000 dilution). Bound IL-6 was detected with 0.16 ng/ml polyhorseradish peroxidase labeled streptavidin (Accurate Chemicals and Scientific, Westbury, NY) and TMB plus hydrogen peroxide substrate (Kirkegaard & Perry Laboratories, Gaithersburg, MD). The sensitivity of the assay is 1–1200 pg.
Immunoprecipitations
Protein synthesis was analyzed by metabolic labeling and immunoprecipitation. Primary chondrocytes were washed in PBS and incubated in cysteine- and methionine-free RPMI 1640 (ICN Biomedicals, Costa Mesa, CA) supplemented with Lglutamine, 1% dialyzed FBS, and [35S]methionine (ICN Biomedicals; 100 µCi/ml) for 24 h. Caspase-1 inhibitor (10 µM; Calbiochem, San Diego, CA) was added with IL-1 in one experiment. The supernatants were collected and incubated with 4 µg rabbit anti-human IL-18 (PeproTech, Rocky Hills, NJ) overnight on a rotor (4°C) and 1.5 h more with goat anti-rabbit Ab coated-agarose beads (Sigma). The precipitates were washed five times with RIPA-M buffer (50 mM Tris (pH 7.4), 50 mM NaCl, 0.5% Nonidet P-40, 1 mM EGTA, 1 mM Na3VO4, 1 mM NaF, 1 µg/ml aprotinin, 1 µg/ml leupeptin, and 1 mM PMSF)). The beads were boiled for 3 min in Laemmli buffer and the proteins were separated on 15% SDS-polyacrylamide gels under reducing conditions. Gels were fixed in 10% acetic acid, treated with Amplify (Amersham, Arlington Heights, IL) for 30 min, dried, and exposed to Kodak XAR film (Eastman Kodak, Rochester, NY) at -70°C for 2–4 days.
Western blot analysis
Cell lysates were prepared for Western blot analysis of iNOS and COXII. Passage 1 chondrocytes were plated and cultured in serum-free media for 24 h. Cells were then cultured with or without IL-1ß (1 ng/ml) for 24 h. After they were washed with cold PBS, the cells were lysed with RIPA-M buffer. The lysates of chondrocytes and standard of iNOS were separated by SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulose membranes (Schleicher & Schuell, Keene, NH). Western blot analysis was performed with primary Abs to iNOS (Transduction Laboratories, Lexington, KY) or COXII (Cayman Chemical, Ann Arbor, MI).
Proteoglycan release from articular cartilage
Pieces of full thickness articular cartilage were incubated for 72 h in the presence of cytokines. Conditioned media were collected and the concentration of sulfated glycosaminoglycans (GAG) was measured using 1,9-dimethylene blue as a monitor of the spectrophotometric changes that occur during the formation of the GAG-SO2 dye complex as described by Goldberg and Kolibas (29). To generate a standard curve, chondroitin sulfate (Sigma) was used at concentrations between 1 and 20 µg/ml.
The statistical significance of the differences in GAG levels was analyzed by paired Student’s t test.
Cytokines
Human rIL-18 was purchased from Peprotech (Rocky Hill, NY). The
ED50 was determined by the stimulation of IFN-
production by human PBMC costimulated with either Con A or PHA is 15
ng/ml. The ED50 of human rIL-1ß (Peprotech) as determined
by the stimulation of [3H]thymidine incorporation by
murine C3H/HeJ thymocytes is 0.1 ng/ml. Endotoxin levels of IL-1 and
IL-18 were less than 0.1 ng per µg of cytokine preparation. In our
experiments, IL-1 was used at 1 ng/ml and IL-18 at 10 ng/ml, thus the
endotoxin contamination level for IL-1 was less than 0.1 pg/ml, whereas
for IL-18 it was less than 1 pg/ml. These levels of endotoxin when
using lipopolysacharide from Salmonella minnesota do not
increase NO production in chondrocytes.
Statistical methods
The significance of difference between group means was determined by a Student’s t test in the program StatView.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Analysis for IL-18 mRNA expression was performed by RT-PCR on a
total of 11 different chondrocyte isolates. Without in vitro
stimulation, IL-18 mRNA was detected in 8 of 11 chondrocyte
preparations. After stimulation with IL-1, all chondrocyte samples
exhibited increased IL-18 mRNA expression; the results from four donors
are shown in Fig. 1
. The time course of
IL-18 mRNA induction by IL-1 varied among donors with some showing peak
expression after 1–2 h whereas this was observed in donor 3 only after
16 h (Fig. 1).
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24 kDa, the molecular mass of pro-IL-18. After
IL-1 stimulation, the intensity of this band increased and a newly
synthesized protein was detected at 18 kDa (Fig. 2), the molecular mass of secreted IL-18.
The IL-18 precursor is processed by caspase-1 to the mature secreted
form (22, 23). To further ascertain that the protein detected was
IL-18, a caspase-1 inhibitor (Ac-Tyr-Val-Ala-Asp-aldehyde) was added to
IL-1-stimulated chondrocytes. The expression of the 18-kDa mature form
IL-18 was completely inhibited by an inhibitor of caspase-1 that did
not alter the levels of the IL-18 precursor (data not shown).
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IL-18 was tested in primary cultures of human articular
chondrocytes for effects on cell proliferation. IL-18 did not stimulate
chondrocyte proliferation. However, IL-18 significantly reduced
chondrocyte proliferation induced by TGF-ß (p
0.03), with inhibition ranging from 30 to 100% (Fig. 3).
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NO is induced by proinflammatory stimuli such as IL-1, TNF-, or
LPS in chondrocytes (11, 12). At the concentration of 10 ng/ml, IL-18
increased NO production in chondrocyte cultures. This was of
borderline significance (p 0.06) when
compared with the control. IL-18 was less potent for the induction of
NO when compared with IL-1ß (Fig. 4).
Chondrocytes from five donors were tested. The results shown represent
average values of NO production from three donors each tested in
duplicate.
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The next series of experiments analyzed potential effects of IL-18
on selected genes that are expressed as part of the known chondrocyte
response to catabolic stimuli such as IL-1 or TNF. RT-PCR was used to
obtain a qualitative assessment of gene expression. IL-18 stimulation
increased the steady-state mRNA levels for iNOS, COXII, IL-6, and
stromelysin (STML) in chondrocytes (Fig. 5). Western blot analysis for iNOS and
COXII showed that IL-18 also increased intracellular levels of these
proteins in chondrocytes (Fig. 6). Using
ELISA, increased levels of IL-6 protein were detected in the
supernatants of chondrocytes stimulated with IL-18 for 24 h (Fig. 7).
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The proteoglycan content in articular cartilage is determined by
the balance between synthesis and degradation. Fresh human articular
cartilage was stimulated in organ culture with IL-18. As shown in Fig. 8, IL-18 at 20 ng/ml significantly
increased the release of proteoglycan from cartilage.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducing factor with functional
similarities to IL-12, IL-18 is predominantly known for its role in
polarizing T cells to a Th1 response (26) and in activating NK cells.
Production of IL-18 has been demonstrated for mononuclear phagocytes
(21), the adrenal cortex, and the neurohypophysis (25). A recent study
suggested a role of IL-18 in mesenchymal cells by demonstrating that
the cytokine is expressed in osteoblast-like stromal cell lines and
suppresses the formation of osteoclasts (24). As IL-1 and IL-1ß
are among the principal catabolic and proinflammatory cytokines in
arthritis (30), the present study analyzed expression and functional
properties of IL-18 in joint tissue cells. The first part of the study examined the regulation of IL-18 expression by chondrocytes. Human articular chondrocytes were found to express IL-18 mRNA. Expression of IL-18 mRNA in chondrocytes isolated from normal articular cartilage in the absence of in vitro stimulation was variable. After in vitro stimulation with IL-1ß, IL-18 mRNA was expressed in all chondrocyte preparations analyzed. The cells also produced IL-18 protein. In immunoprecipitates of chondrocytes, two forms of IL-18 were detected, the precursor with a molecular mass of 24 kDa and the mature form of 18 kDa. The synthesis of both forms was increased by IL-1 stimulation and processing of the precursor to the mature form was prevented by an inhibitor of caspase-1, previously known as IL-1 converting enzyme. Thus, in addition to mononuclear phagocytes, chondrocytes are potential sources of IL-18 in the joint. The present study did not address expression of IL-18 protein or mRNA directly in noncultured tissues from arthritis patients, but a preliminary report indicates that rheumatoid arthritis synovial tissue cells express IL-18 mRNA and spontaneously produce IL-18 protein in vitro (31).
The second part of the present study examined the role of IL-18 in the
regulation of cell proliferation and secretory function of human
articular chondrocytes. In chondrocytes, IL-18 inhibited cell
proliferation induced by TGF-ß, one of the major growth factors for
these cells (18). IL-18 thus shares at least one effect with IL-1 on
chondrocytes; it antagonized the action of TGF-ß. IL-18 was found to
be a regulator of gene expression and secretory function in
chondrocytes. Representative examples of genes whose products are
involved in the pathogenesis of different aspects of arthritis were
analyzed. This demonstrated that IL-18 induces or increases the
expression of mRNAs for iNOS and COXII, the enzymes responsible for the
production of NO and PG. Expression of these mRNAs was associated with
the increased synthesis of intracellular iNOS and COXII proteins. We
also demonstrated increased release of NO with a borderline
significance (p 0.06) in IL-18-stimulated
chondrocyte and cartilage cultures. NO is thought to be involved in the
pathogenesis of arthritis through the suppression of proteoglycan
synthesis (32), disruption of integrin signaling, inhibition of
chondrocyte migration (33, 34), and the induction of chondrocyte
apoptosis (14). PG are thought to be involved in the pathogenesis of
arthritis by increasing local blood flow and vascular permeability
(35). IL-18 also stimulated cytokine gene expression and protein
secretion in chondrocytes as demonstrated in this study for IL-6.
The potential of IL-18 to contribute to the degradation of cartilage extracellular matrix was demonstrated by the induction of mRNA for stromelysin in articular chondrocytes. Additional evidence for catabolic effects of IL-18 was obtained in cultures of cartilage that released GAG after IL-18 stimulation.
As IL-18 could induce the expression of IL-1ß and TNF- mRNA and
the latter two cytokines have qualitatively similar effects on
chondrocytes as IL-18, it was possible that the IL-18 effects were
dependent on or mediated by the release of IL-1 or TNF. To address
this, chondrocytes were treated with IL-18 in the presence of
neutralizing Abs to IL-1ß or TNF-. The TNF neutralizing Ab caused
a modest decrease in the IL-18-induced NO production, whereas the IL-1
neutralizing Ab had no detectable inhibitory effect (data not shown).
These findings suggest that the IL-18 effects are not IL-1 dependent
and depend to a modest degree on TNF-. Additional support for a
direct IL-18 effect on chondrocytes was obtained with kinase assays.
IL-18 caused an increase in the phosphorylation of the MAP kinases p38
and JNK within 15 min (T.O., unpublished observations).
The IL-18R is a member of the IL-1R family but IL-1 does not compete
binding of IL-18 to its receptor (27). Furthermore, transfection of the
IL-18R was sufficient to induce intracellular signals as indicated by
the activation of NF-
B, suggesting that the IL-1R accessory protein
that is required for IL-1 action is not part of the IL-18R. Thus, at
least at the receptor level and at the very proximal events of
intracellular signaling, there are differences between IL-1 and IL-18.
In conclusion, this study indicates that human articular chondrocytes produce IL-18 mRNA and protein. IL-18 activates chondrocytes in a pattern qualitatively similar to IL-1, but IL-18 appears to be less potent as compared with IL-1. These findings characterize IL-18 as a new cytokine that can contribute to cartilage degradation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to M. Lotz, Division of Arthritis Research, SBR7, The Scripps Research Institute, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: COXII, cyclooxygenase; NO, nitric oxide; iNOS, inducible nitric oxide synthase; GAG, glycosaminoglycans
Received for publication May 7, 1998. Accepted for publication October 2, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E. Esfandiari, I. B. McInnes, G. Lindop, F.-P. Huang, M. Field, M. Komai-Koma, X.-q. Wei, and F. Y. Liew A Proinflammatory Role of IL-18 in the Development of Spontaneous Autoimmune Disease J. Immunol., November 1, 2001; 167(9): 5338 - 5347. [Abstract] [Full Text] [PDF]
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B. P. Leung, S. Culshaw, J. A. Gracie, D. Hunter, C. A. Canetti, C. Campbell, F. Cunha, F. Y. Liew, and I. B. McInnes A Role for IL-18 in Neutrophil Activation J. Immunol., September 1, 2001; 167(5): 2879 - 2886. [Abstract] [Full Text] [PDF]
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C. C. Park, J. C. M. Morel, M. A. Amin, M. A. Connors, L. A. Harlow, and A. E. Koch Evidence of IL-18 as a Novel Angiogenic Mediator J. Immunol., August 1, 2001; 167(3): 1644 - 1653. [Abstract] [Full Text] [PDF]
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 O. Yoshino, Y. Osuga, K. Koga, O. Tsutsumi, T. Yano, T. Fujii, K. Kugu, M. Momoeda, T. Fujiwara, K. Tomita, et al. Evidence for the expression of interleukin (IL)-18, IL-18 receptor and IL-18 binding protein in the human endometrium Mol. Hum. Reprod., July 1, 2001; 7(7): 649 - 654. [Abstract] [Full Text] [PDF]
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B. Moller, N. Kukoc-Zivojnov, U. Kessler, S. Rehart, J. P. Kaltwasser, D. Hoelzer, U. Kalina, and O. G. Ottmann Expression of interleukin-18 and its monokine-directed function in rheumatoid arthritis Rheumatology, March 1, 2001; 40(3): 302 - 309. [Abstract] [Full Text] [PDF]
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L. A. B. Joosten, F. A. J. van de Loo, E. Lubberts, M. M. A. Helsen, M. G. Netea, J. W. M. van der Meer, C. A. Dinarello, and W. B. van den Berg An IFN-{gamma}-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis J. Immunol., December 1, 2000; 165(11): 6553 - 6558. [Abstract] [Full Text] [PDF]
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H. Lu, C. Shen, and R. C. Brunham Chlamydia trachomatis Infection of Epithelial Cells Induces the Activation of Caspase-1 and Release of Mature IL-18 J. Immunol., August 1, 2000; 165(3): 1463 - 1469. [Abstract] [Full Text] [PDF]
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B. P. Leung, I. B. McInnes, E. Esfandiari, X.-Q. Wei, and F. Y. Liew Combined Effects of IL-12 and IL-18 on the Induction of Collagen-Induced Arthritis J. Immunol., June 15, 2000; 164(12): 6495 - 6502. [Abstract] [Full Text] [PDF]
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M. G. Attur, M. N. Dave, R. M. Clancy, I. R. Patel, S. B. Abramson, and A. R. Amin Functional Genomic Analysis in Arthritis-Affected Cartilage: Yin-Yang Regulation of Inflammatory Mediators by {alpha}5{beta}1 and {alpha}V{beta}3 Integrins J. Immunol., March 1, 2000; 164(5): 2684 - 2691. [Abstract] [Full Text] [PDF]
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 I. A. Schrijver, M.-J. Melief, M. van Meurs, A. R. Companjen, and J. D. Laman Pararosaniline Fixation for Detection of Co-stimulatory Molecules, Cytokines, and Specific Antibody J. Histochem. Cytochem., January 1, 2000; 48(1): 95 - 104. [Abstract] [Full Text]
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L. L. Reznikov, S.-H. Kim, J. Y. Westcott, J. Frishman, G. Fantuzzi, D. Novick, M. Rubinstein, and C. A. Dinarello IL-18 binding protein increases spontaneous and IL-1-induced prostaglandin production via inhibition of IFN-gamma PNAS, February 29, 2000; 97(5): 2174 - 2179. [Abstract] [Full Text] [PDF]
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