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-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis
*
Rheumatology Research Laboratory and
Department of Internal Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands; and
Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80261
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducing
factor and is a pivotal cytokine for the development of Th1 responses.
Apart from Th1 immune-stimulatory activity, IL-18 induces the
production of proinflammatory cytokines such as TNF-
and IL-1 in
vitro. The goal was to investigate the role of endogenous IL-18 in
murine streptococcal cell wall (SCW)-induced arthritis. Furthermore, we
investigated whether IL-18 neutralization had an impact on local TNF
and IL-1 production. C57BL/6, BALB/c, and IFN--deficient mice were
injected with 2 mg of rabbit anti-murine IL-18 Abs shortly before
induction of arthritis by intra-articular injection of 25 µg of SCW
fragments into the right knee joint. Suppression of joint swelling was
noted on days 1 and 2 of SCW arthritis after blockade of endogenous
IL-18. Analysis of local cytokine concentrations showed that IL-18,
TNF-, and IL-1
levels were decreased. Severe inhibition of
chondrocyte proteoglycan synthesis was seen in the vehicle-treated
control animals, whereas a reversal of the inhibition of chondrocyte
proteoglycan synthesis was found in the anti-IL-18-exposed animals.
Blockade of endogenous IL-18 in IFN--deficient mice showed results
similar to those found in wild-type animals, identifying a role for
IL-18 that is IFN- independent. The present study indicates that
IL-18 is a proinflammatory cytokine during the onset of murine SCW
arthritis, and this inflammatory role of IL-18 is IFN-
independent. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-inducing factor, is a pivotal cytokine for the development of
Th1 responses (1, 2). IL-18 is structurally related to
IL-1; both cytokines need IL-1-converting enzyme
(ICE2 or caspase-1)
for cleavage of the precursor to release the bioactive molecules for
IL-1 and IL-18 (3, 4). Functionally, IL-18 and IL-1
display similar activities. Both cytokines act as costimuli of IFN-
production and are direct proinflammatory cytokines. IL-18 is also
related to IL-12. Both cytokines are currently regarded as inducers of
IFN- production during innate and adaptive immune responses
(5). Remarkable synergism between IL-12 and IL-18 is found
concerning IFN- production, which is due to up-regulation of the
IL-18R by IL-12 (6, 7). IL-12-induced IFN- production
is dependent on ICE-mediated cleavage of the precursor IL-18
(8). In addition, IFN- production is almost absent in
IL-18-deficient mice and ICE-deficient mice (9, 10). Apart
from immune-stimulatory activity, IL-18 induces the production of
proinflammatory cytokines such as TNF- and IL-1 in vitro
(11). Furthermore, it has been shown that IL-18 activates
NF-
B and induces chemokines such as IL-8 and macrophage inflammatory
protein-1 (12).
In several diseases, including rheumatoid arthritis (RA), IL-18 is
considered as a proinflammatory cytokine (13). IL-18 is
expressed in human RA synovium, and enhanced levels of IL-18 were found
in the sera of RA patients (14). IL-18 synthesis is found
in both articular chondrocytes and osteoblasts, and with respect to
cartilage, IL-18 promotes gene expression of NO synthase, inducible
cyclo-oxygenase, IL-6, and stromelysin (15, 16).
Interestingly, strong synergism was found for the actions of IL-12,
IL-15, and IL-18 on both IFN- and TNF- production by RA synovial
membrane cultures (14). In line with these findings,
combined IL-12 and IL-18 administration accelerates the induction of
murine collagen-induced arthritis, probably related to enhancement of
Th1 reactivity (17). At present, no in vivo studies have
been performed to explore the role of endogenous IL-18 in arthritis
models. Apart from a contribution in Th1-driven processes, IL-18 may
potentially promote macrophage-driven TNF and IL-1 production.
Murine streptococcal cell wall (SCW) arthritis is an acute animal model
of arthritis that can be induced by a single intra-articular injection
of bacterial cell wall fragments into a knee joint of a naive mouse
(18). It has been shown that TNF- and IL-1 play a
different role in SCW arthritis. While TNF- mediates joint swelling,
IL-1 is crucial for cartilage destruction (19).
Furthermore, IL-10 controls the severity of SCW arthritis, because
anti-IL-10 treatment aggravates SCW arthritis (20). In
addition, anti-IL-12 treatment suppresses joint swelling
(21). Because IL-18 is produced by macrophages after
stimulation with bacterial compounds (22), it is likely
that IL-18 is involved in the onset of murine SCW arthritis.
The goal of the present study was to investigate the role of IL-18 in
this nonimmune experimental arthritis model. To this end we neutralized
endogenous IL-18 before the induction of SCW arthritis and determined
the effect on joint pathology. The effect of IL-18 blockade was
compared with that of TNF- or IL-1 elimination. Furthermore, we
analyzed the impact of IL-18 blockade on TNF and IL-1 production. In
addition, we explored whether IL-18 displays proinflammatory aspects
independently of IFN- induction, using IFN--deficient
mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/6 and BALB/c mice were obtained from Charles River
(Sulzfeld, Germany). IFN--deficient mice
(BALB/c-Ifngtm1Ts) were purchased from The
Jackson Laboratory (Bar Harbor, ME) in conjunction with NV Organon
(Oss, The Netherlands). The mice were housed in filter-top cages, and
water and food were provided ad libitum. The mice were used
at 10–12 wk of age.
Materials
Ethidium bromide, rabbit Igs, and BSA were purchased from Sigma
(St. Louis, MO). RPMI 1640 medium, Taq DNA polymerase, 100-bp DNA
marker, TRIzol reagent, and agarose were obtained from Life
Technologies (Breda, The Netherlands). GAPDH and IL-18 primers were
purchased from Eurogentec (Seraing, Belgium). Murine IL-1 receptor
antagonist (Ra) capture (MAP480) and detection (BAF480) Abs and
recombinant murine IL-1Ra were obtained from R&D Systems (Abingdon,
U.K.). The murine IL-18 ELISA kit was purchased from R&D Systems.
Radioactive [35S]sulfate was purchased from NEN
Life Sciences Products (Boston, MA). The anti-IL-18 antiserum was
obtained from a New Zealand rabbit immunized by intradermal injection
of murine IL-18 (PeproTech, Princeton, NJ) in the presence of Hunter’s
Titermax adjuvant (CytRx, Norcross, GA). This Ab has been shown to
inhibit LPS-induced IFN- production in vivo (10).
Rabbit anti-murine TNF- Abs (AMC3012) were obtained from
BioSource (Camarillo, CA). Rabbit anti-murine IL-1 and IL-1
were generated by Dr. F. A. J. van de Loo (23).
Rat anti-murine IFN- Abs (R46A2) were provided by Dr. W. Falk,
University of Regensburg (Regensburg, Germany) (24).
SCW preparation and induction of SCW arthritis
Streptococcus pyogenes T12 organisms were cultured overnight in Todd-Hewitt broth. Cell walls were prepared as described previously (18). The resulting 10,000 x g supernatant was used throughout the experiments. These preparations contained 11% muramic acid. Unilateral arthritis was induced by intra-articular injection of 25 µg of SCW (rhamnose content) in 5 µl of PBS into the right knee joints of naive mice. As a control, PBS was injected into the left knee joints.
Anti-IL-18, anti-TNF-, anti-IL-1,, and
anti-IFN- treatment of SCW arthritis
To neutralize endogenous IL-18, TNF-, IL-1, and IL-1,
C57BL/6 mice were i.p. injected with 2 mg of rabbit anti-murine
IL-18, rabbit anti-murine TNF-, and rabbit anti-murine
IL-1 and IL-1 Abs 2 h before induction of SCW arthritis. As
control we injected i.p. 2 mg of rabbit Igs. To confirm the data found
in the IFN--deficient mice, C57BL/6 mice were i.p. injected with 100
µg of rat anti-murine IFN- Abs 3 h before induction of
SCW arthritis. One hour later the mice were injected with either
anti-IL-18 or control Igs.
Measurement of joint inflammation
SCW arthritis was quantified by the 99mTc uptake method (25). This method measures, by external gamma counting, the accumulation of a small radioisotope at the site of inflammation due to local increased blood flow and tissue swelling. The severity of inflammation is expressed as the ratio of 99mTc uptake in the right (inflamed) over the left (control) knee joint. All values exceeding 1.10 were designated inflammation.
Chondrocyte proteoglycan (PG) synthesis determination
Patellae with minimal surrounding tissue, were placed in RPMI 1640 medium with Glutamax (Life Technologies, Paisley, U.K.), penicillin/streptomycin (100 IU/100 µg/ml) and [35S]sulfate (0.74 MBq/ml). After a 3-h incubation at 37°C in a CO2 incubator, patellae were washed in saline three times, fixed in 4% formaldehyde, and subsequently decalcified in 5% formic acid for 4 h. Patellae were punched out of the adjacent tissue and dissolved in 0.5 ml of Luma Solve (Ominlabo, Breda, The Netherlands) at 65°C; after addition of 10 ml of Lipoluma (Omnilabo) the 35S content was measured by liquid scintillation counting. Values are presented as the percent 35S incorporation in the left control joint.
Cytokine measurements
To determine the levels of IL-18, TNF-, IL-1, or IL-1Ra in
patellae washouts, patellae were isolated from inflamed knee joints as
previously described (19, 21). Patellae were cultured in
RPMI 1640 medium containing 0.1% BSA (200 µl/patella) for 1 h
at room temperature. Thereafter, supernatant was harvested and
centrifuged for 5 min at 1000 x g. TNF- and IL-1
were determined by RIA (26). IL-18 and IL-1Ra levels were
measured by ELISA. The sensitivities of the ELISA for IL-18 and IL-1Ra
and of the RIA for TNF- and IL-1 are 160, 80, 40, and 20 pg/ml,
respectively. Cytokine levels reflects the diffusion of presynthesized
protein, because no difference was observed between samples obtained at
4 and 37°C. Addition of rabbit anti-IL-18 to the standard curve
did not interfere with the IL-18 ELISA.
RNA isolation
Mice were killed by cervical dislocation, immediately followed by dissection of the patella with adjacent synovium (27). From six patella specimens synovium biopsies were taken. Two biopsies (diameter, 3 mm) were punched out using a biopsy punch (Stiefel, Wachtersbach, Germany): one from the lateral and one from the medial side. Six patella specimens per experimental group were taken, and three lateral and three medial biopsies were pooled to yield two samples per group. The synovium samples, containing synovial membrane cells, infiltrating cells, and muscle cells, were immediately frozen in liquid nitrogen. Synovium biopsies were ground to powder using a Microdismembrator II (Braun, Melsungen, Germany). Total RNA was extracted in 1 ml of TRIzol reagent, an improved single-step RNA isolation method based on the method described by Chomczynski and Sacchi (28).
PCR amplification
One microgram of synovial RNA was used for RT-PCR. mRNA was reverse transcribed to cDNA using oligo(dT) primers and 1/20th of the cDNA was used in one PCR amplification. PCR was performed at a final concentration of 200 µM dNTPs, 0.1 µM of each primer, and 1 U of Taq polymerase in standard PCR buffer. The mixture was overlaid with mineral oil and amplified in a thermocycler (Omnigene, Hybaid, Ashford, U.K.). Message for GAPDH and IL-18 was amplified using the primers previously described (29, 30). Samples of 5 µl were taken from the reaction tubes after a certain number of cycles. PCR products were separated on 1.6% agarose and stained with ethidium bromide.
Statistical analysis
Differences between experimental groups were tested using the Mann-Whitney U test unless stated otherwise.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine SCW arthritis is induced by a single injection of SCW
fragments into a mouse knee joint. This leads to an acute inflammation,
characterized by joint swelling and inhibition of matrix production of
chondrocytes in the articular cartilage. Significant joint swelling was
found up to 7 days after injection of SCW fragments. Severe inhibition
of chondrocyte PG synthesis was noted on days 1, 2, and 4 (Fig. 1
). Massive influx of polymorphonuclear
cells in the joint cavity and synovial membrane was seen on day 1 and
2, as recently described (19, 21).
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The local cytokine pattern was analyzed during the first stage of
SCW arthritis by analysis of synovial tissue washouts. Remarkably, high
levels of IL-18 were already detectable in patella washouts of naive
mice compared with TNF and IL-1 levels (Table I). IL-18 levels were 2-fold increased at
both 90 min and 4 h after induction of arthritis compared with
those in naive mice. Even more elevated levels of IL-18 were found on
days 1 and 2. This was in line with RT-PCR analysis of synovial
biopsies, which showed that IL-18 mRNA levels were up-regulated on days
1 and 2 (Fig. 2). The highest level of
TNF- (550 ± 70 pg/ml) was found at 90 min after induction of
arthritis, whereas the maximum IL-1 level (1500 ± 250 pg/ml)
was found at 4 h. In contrast to the small increase in IL-18, both
TNF- and IL-1 were strongly up-regulated compared with the levels
found in naive joints.
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To examine the effect of neutralization of endogenous IL-18 on SCW
arthritis, we injected rabbit anti-murine IL-18 Abs i.p. 2 h
before induction of SCW arthritis. To compare IL-18 elimination with
TNF- or IL-1 blocking, we also injected rabbit anti-murine
TNF- or rabbit anti-murine IL-1 and IL-1 in separate
groups of mice. A strong reduction of joint swelling was noted after
IL-18 blockade compared with that in the control Ig-treated animals on
both days 1 and 2 (Fig. 3).
Interestingly, IL-18 blockade was more effective in the reduction of
joint swelling than TNF- neutralization. In contrast to IL-18
blockade, IL-1 elimination did not reduce joint swelling compared with
control treatment.
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To investigate whether anti-IL-18 treatment influenced local
cytokine levels, we analyzed synovial washouts at several time points
after induction of SCW arthritis. At 90 min we found that local IL-18,
TNF-, and IL-1 levels were strongly reduced after blockade of
endogenous IL-18 (Table II). Synovial
IL-18, TNF-, and IL-1 levels were still reduced in the
anti-IL-18-treated animals at 4 h. Of interest, IL-1 levels
were reduced up to day 1 (Table II). Of importance, local IL-1Ra levels
determined on day 1 were enhanced by 2- to 3-fold compared with those
after control treatment (550 ± 110 vs 190 ± 70 pg/ml).
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Due to the inflammatory process in the joint, chondrocyte matrix
production is strongly inhibited, as reflected by reduced chondrocyte
PG synthesis (Figs. 1
and 4). Chondrocyte
synthetic activity after SCW injection was restored to normal after
anti-IL-18 on day 1, whereas a diminished inhibition of the
chondrocyte matrix production was found on day 2 (Fig. 4). The
favorable shift in the IL-1Ra/IL-1 balance could explain the
unaffected chondrocyte synthetic function on day 1 of SCW arthritis
after neutralization of endogenous IL-18.
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-independent role for IL-18 in SCW arthritis
As previously described IFN- is produced during the onset of
SCW arthritis (21). The highest levels of IFN- (up to
60 pg/ml) were noted at 4 h after injection of SCW fragments.
Because IL-18 induces IFN- in several cell types, including
macrophages, we examined whether IL-18 mediates its proinflammatory
role by the induction of IFN-. To this end we included
IFN--deficient mice in our study. First, we analyzed local IL-1,
IL-18, and TNF- levels in the IFN--deficient mice shortly after
the induction of SCW arthritis. As shown in Table III local levels of IL-1, IL-18, and
TNF- were comparable in the two mouse strains. Fig. 5 shows that there was no difference in
joint swelling and inhibition of chondrocyte PG synthesis between
wild-type and IFN--deficient mice on day 1 of SCW arthritis.
Anti-IL-18 treatment revealed an IFN--independent pathway for IL-18
during the onset of murine SCW arthritis. Both joint swelling and
chondrocyte function were similarly affected by blockade of endogenous
IL-18. Further evidence of the IFN--independent role of IL-18 was
obtained using neutralizing Abs directed against murine IFN-.
Roughly the same data were found compared with the results obtained in
the IFN--deficient mice (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and IL-1. A remarkable
finding was that the proinflammatory role of IL-18 in the onset of this
model was IFN- independent. SCW arthritis is an experimental model of arthritis in which macrophages play an important role. It has been shown that bacterial cell wall fragments (peptidoglycan) induced production of a wide range of proinflammatory cytokines by macrophages in vitro. Using these fragments in vivo, for induction of acute or chronic arthritis in animals, enhanced levels of cytokines and chemokines were found (19, 21, 31). Here we demonstrated for the first time that IL-18 levels are already high in normal tissue but are clearly up-regulated on both protein and mRNA levels during the onset of SCW arthritis. Compared with TNF or IL-1, IL-18 levels were slightly enhanced shortly after onset (10- vs 2-fold enhancement compared with the naive joint). In line with these data, IL-18 levels (342 pg/ml) in synovial fluid of RA patients were also slightly elevated, compared with IL-18 levels in the sera of RA patients and healthy controls (50–150 pg/ml) (14).
As shown previously TNF- is the major cytokine responsible for the
acute joint swelling in SCW arthritis (19, 32). The
pivotal role of TNF- in the early joint swelling was corroborated by
elegant studies of SCW arthritis in TNF--deficient mice
(33). The major role of TNF- in early joint swelling
was also noted in the onset of murine collagen-induced arthritis
(34, 35). Blockade of endogenous IL-18 resulted in clear
suppression of joint swelling on days 1 and 2 of SCW arthritis. This
coincided with a marked reduction of TNF-, which is likely to be
responsible for the suppression of joint swelling.
Inhibition of chondrocyte PG synthesis in the arthritic cartilage is a
common feature seen in experimental arthritis models, and IL-1 is the
pivotal cytokine responsible for this inhibition (23). In
the present study it was shown that neutralization of IL-18 during the
onset results in full protection against inhibition of chondrocyte
anabolic function on day 1 of acute SCW arthritis and significant
reduction on day 2. IL-1 levels were markedly reduced by
anti-IL-18 treatment, in particular shortly after induction of SCW
arthritis. Furthermore, the balance of IL-1/IL-1Ra was improved on
day 1 after anti-IL-18 exposure, which may be the mechanism of the
protective effect on chondrocyte PG synthesis. Earlier studies showed
that blockade of IL-1 activity by application of rIL-1Ra completely
prevented inhibition of chondrocyte PG synthesis during acute SCW
arthritis (19). IL-18 itself can also cause inhibition of
chondrocyte metabolism as recently demonstrated (16).
Therefore, it is likely that both reduced IL-1 levels as well as IL-18
blockade contributed to the protection of chondrocyte metabolism. It
would be interesting to test the potential efficacy of ICE inhibitors
in SCW arthritis. ICE is needed for the generation of both IL-1 and
IL-18 and this blockade might provide a dual hit. It was already shown
that ICE blockers were effective in murine collagen-induced
arthritis, which was claimed to prove IL-1 involvement, but may reflect
an IL-18 component as well (36).
Recently, it was demonstrated that inhibition of chondrocyte PG
synthesis induced by IL-1 was mediated by NO, because NOS2-deficient
mice were revealed to be resistant to this effect (37, 38). IL-18 exposure of chondrocytes leads to enhanced iNOS mRNA
levels and NO production (16). Blocking of endogenous
IL-18 may have a beneficial effect on NO levels by both reduction of
IL-1 and inactivation of IL-18, resulting in protected chondrocyte PG
synthesis. Cytokine-induced NO synthesis by macrophages, synoviocytes,
and chondrocytes is strongly enhanced by IFN-. Furthermore,
synergistic effects on inhibition of chondrocyte PG synthesis between
IL-1 and several other cytokines, such as TNF- and IFN-, were
demonstrated (39, 40).
IL-18 itself can induce IFN-, but impressive synergy on IFN-
production was seen with IL-12. As shown previously, IL-12 levels are
increased during the onset of SCW arthritis (21).
Therefore, it may be expected that IFN- plays an important role in
IL-18-mediated processes. Here we demonstrated an IFN--independent
pathway of IL-18 during the onset of SCW arthritis. This was proven by
blockade of IL-18 during induction of SCW arthritis in
IFN--deficient mice, showing no difference between IFN--deficient
and wild-type mice. The latter studies were corroborated by the use of
neutralizing anti-murine IFN- Abs. Recently, IFN--independent
IL-18 effects were described in other models, such as lethal
Salmonella typhimurium endotoxemia and IL-18/IL-12 lethal
toxicity (41, 42).
IL-18 is found in chronic processes, such as RA and Crohn’s disease
(14, 43). In both diseases, IL-18 is up-regulated, and
local factors, such as TNF and IL-1, may be involved in IL-18 gene
expression. IL-18 together with IL-12 and IL-15 might be one of the
crucial factors that drive the local Th1 response. It is known that
IL-12 itself can unmask Th1 autoimmune responses and may be involved in
the onset of chronic diseases such as RA (44). IL-15 is
present in RA synovial tissue, in which it activates T cells and
macrophages to produce proinflammatory cytokines (45, 46).
IL-18 is considered a pivotal cytokine regarding IFN- production and
polarization of Th1 responses. However, levels of IFN- are
relatively low in RA synovial tissues, and novel IFN- independent
pathways of IL-18 may be important targets in RA. Blocking of IL-18 may
be beneficial for regulating Th1 responses. Recently, IL-18 binding
protein (IL-18BP) was described as a novel modulator of the Th1
cytokine response (47). In animal models IL-18BP
administration blocks 90% of the IFN- production after LPS
injections. IL-18BP is a member of a family of secreted proteins that
includes several poxvirus proteins. These proteins inactivated IL-18
and inhibited the NK cell response (48). It remains to be
investigated whether IL-18BP or novel poxvirus proteins might be useful
for the treatment of Th1-related diseases.
The present study indicates that IL-18 is a primary proinflammatory cytokine during the onset of bacterial cell wall-induced arthritis. Blockade of IL-18 ameliorates joint pathology by reducing TNF and IL-1 levels. Anti-IL-18 therapy could be efficacious in the treatment of patients with arthritis.
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Footnotes |
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2 Abbreviations used in this paper: ICE, IL-1-converting enzyme; RA, rheumatoid arthritis; SCW, streptococcal cell wall; PG, proteoglycan; IL-18BP, IL-18 binding protein; Ra, receptor antagonist.
Received for publication July 28, 2000. Accepted for publication September 8, 2000.
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C. A. Cannetti, B. P. Leung, S. Culshaw, I. B. McInnes, F. Q. Cunha, and F. Y. Liew IL-18 Enhances Collagen-Induced Arthritis by Recruiting Neutrophils Via TNF-{alpha} and Leukotriene B4 J. Immunol., July 15, 2003; 171(2): 1009 - 1015. [Abstract] [Full Text] [PDF]
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N. K. Banda, A. Vondracek, D. Kraus, C. A. Dinarello, S.-H. Kim, A. Bendele, G. Senaldi, and W. P. Arend Mechanisms of Inhibition of Collagen-Induced Arthritis by Murine IL-18 Binding Protein J. Immunol., February 15, 2003; 170(4): 2100 - 2105. [Abstract] [Full Text] [PDF]
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M. Komai-Koma, J. A. Gracie, X.-q. Wei, D. Xu, N. Thomson, I. B. McInnes, and F. Y. Liew Chemoattraction of Human T Cells by IL-18 J. Immunol., January 15, 2003; 170(2): 1084 - 1090. [Abstract] [Full Text] [PDF]
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F Y Liew and I B McInnes Role of interleukin 15 and interleukin 18 in inflammatory response Ann Rheum Dis, November 1, 2002; 61(90002): ii100 - 102. [Abstract] [Full Text] [PDF]
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 R. J. L. Stuyt, M. G. Netea, I. Verschueren, G. Fantuzzi, C. A. Dinarello, J. W. M. Van der Meer, and B. J. Kullberg Role of Interleukin-18 in Host Defense against Disseminated Candida albicans Infection Infect. Immun., June 1, 2002; 70(6): 3284 - 3286. [Abstract] [Full Text] [PDF]
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