title: An IFN-gamma-independent proinflammatory role of IL-18 in murine streptococcal cell wall arthritis.
abstract: 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 microg 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-1ss 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.
authors.affiliation: Rheumatology Research Laboratory and Department of Internal Medicine, University Medical Center St. Radboud, Nijmegen, The Netherlands. l.joosten@reuma.azn.nl
authors.forename: L A
authors.initials: LA
authors.lastname: Joosten
authors.forename: F A
authors.initials: FA
authors.lastname: van De Loo
authors.forename: E
authors.initials: E
authors.lastname: Lubberts
authors.forename: M M
authors.initials: MM
authors.lastname: Helsen
authors.forename: M G
authors.initials: MG
authors.lastname: Netea
authors.forename: J W
authors.initials: JW
authors.lastname: van Der Meer
authors.forename: C A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: W B
authors.initials: WB
authors.lastname: van Den Berg
mesh_terms: D000818:Animals; D001170:Arthritis, Infectious / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D002473:Cell Wall / Q000276:immunology; D019902:Chondrocytes / Q000378:metabolism; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016326:Extracellular Matrix Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007106:Immune Sera / Q000008:administration & dosage; D018836:Inflammation Mediators / Q000276:immunology*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000502:physiology*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013290:Streptococcal Infections / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D013297:Streptococcus pyogenes / Q000276:immunology*
chemical_list: D016207:Cytokines; D016326:Extracellular Matrix Proteins; D007106:Immune Sera; D018836:Inflammation Mediators; D020382:Interleukin-18; D007371:Interferon-gamma