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The Journal of Immunology, 2000, 165: 6553-6558.
Copyright © 2000 by The American Association of Immunologists

An IFN-{gamma}-Independent Proinflammatory Role of IL-18 in Murine Streptococcal Cell Wall Arthritis

Leo A. B. Joosten1,*, Fons A. J. van de Loo*, Erik Lubberts*, Monique M. A. Helsen*, Mihai G. Netea{dagger}, Jos W. M. van der Meer{dagger}, Charles A. Dinarello{ddagger} and Wim B. van den Berg*

* Rheumatology Research Laboratory and {dagger} Department of Internal Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands; and {ddagger} Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO 80261

IL-18 is a member of the IL-1 family of proteins that exerts proinflammatory effects. It was formally known as IFN-{gamma}-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-{alpha} 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-{gamma}-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-{alpha}, and IL-1{beta} 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-{gamma}-deficient mice showed results similar to those found in wild-type animals, identifying a role for IL-18 that is IFN-{gamma} 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-{gamma} independent.




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