Interleukin-18 promotes joint inflammation and induces interleukin-1-driven cartilage destruction.
Interleukin (IL)-18 is a member of the IL-1 family of proteins that exerts proinflammatory effects and is a pivotal cytokine for the development of Th1 responses. The goal of the present study was to investigate whether IL-18 induces joint inflammation and joint destruction directly or via induction of other cytokines such as IL-1 and tumor necrosis factor (TNF). To this end we performed both in vitro and in vivo kinetic studies. For in vivo IL-18 exposure studies C57BL/6, TNF-deficient, and IL-1-deficient mice were injected intra-articularly with 1.10(7) pfu mIL-18 adenovirus followed by histopathological examination. Local overexpression of IL-18 resulted in pronounced joint inflammation and cartilage proteoglycan loss in control mice. Of high interest, IL-18 gene transfer in IL-1-deficient mice did not show cartilage damage, although joint inflammation was similar to that in wild-type animals. Overexpression of IL-18 in TNF-deficient mice showed that TNF was partly involved in IL-18-induced joint swelling and influx of inflammatory cells, but cartilage proteoglycan loss occurred independent of TNF. In vitro cartilage degradation by IL-18 was found after a 72-hour culture period. Blocking of IL-1 with IL-1Ra or an ICE-inhibitor resulted in complete protection against IL-18-mediated cartilage degradation. The present study demonstrated that IL-18 induces joint inflammation independently of IL-1. In addition, we showed that IL-1beta generation, because of IL-18 exposure, was essential for marked cartilage degradation both in vitro and in vivo. These findings implicate that IL-18, in contrast to TNF, contributes through separate pathways to joint inflammation and cartilage destruction.
Joosten
Leo A B
LA
Rheumatology Research Laboratory and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. l.joosten@reuma.umcn.nl
Smeets
Ruben L
RL
Koenders
Marije I
MI
van den Bersselaar
Liduine A M
LA
Helsen
Monique M A
MM
Oppers-Walgreen
Birgitte
B
Lubberts
Erik
E
Iwakura
Yoichiro
Y
van de Loo
Fons A J
FA
van den Berg
Wim B
WB
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D007375:Interleukin-1 / Q000235:genetics / Q000502:physiology*; D020382:Interleukin-18 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011509:Proteoglycans / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D015843:Serpins / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology; D014764:Viral Proteins
D007375:Interleukin-1; D020382:Interleukin-18; D011509:Proteoglycans; D017472:Receptors, Interleukin-1; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor