The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models.
Interleukin-17 (IL-17) is a T cell cytokine spontaneously produced by cultures of rheumatoid arthritis (RA) synovial membranes. High levels have been detected in the synovial fluid of patients with RA. The trigger for IL-17 is not fully identified; however, IL-23 promotes the production of IL-17 and a strong correlation between IL-15 and IL-17 levels in synovial fluid has been observed. IL-17 is a potent inducer of various cytokines such as tumor necrosis factor (TNF)-alpha, IL-1, and receptor activator of NF-kappaB ligand (RANKL). Additive or even synergistic effects with IL-1 and TNF-alpha in inducing cytokine expression and joint damage have been shown in vitro and in vivo. This review describes the role of IL-17 in the pathogenesis of destructive arthritis with a major focus on studies in vivo in arthritis models. From these studies in vivo it can be concluded that IL-17 becomes significant when T cells are a major element of the arthritis process. Moreover, IL-17 has the capacity to induce joint destruction in an IL-1-independent manner and can bypass TNF-dependent arthritis. Anti-IL-17 cytokine therapy is of interest as an additional new anti-rheumatic strategy for RA, in particular in situations in which elevated IL-17 might attenuate the response to anti-TNF/anti-IL-1 therapy.
Lubberts
Erik
E
Department of Rheumatology, Rheumatology Research and Advanced Therapeutics, University Medical Center Nijmegen, Nijmegen, The Netherlands. E.Lubberts@reuma.umcn.nl
Koenders
Marije I
MI
van den Berg
Wim B
WB
D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D001327:Autoimmune Diseases / Q000503:physiopathology; D001842:Bone and Bones / Q000473:pathology; D002352:Carrier Proteins / Q000502:physiology; D002358:Cartilage, Articular / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000502:physiology*; D007378:Interleukins / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D009504:Neutrophils / Q000473:pathology; D010010:Osteoclasts / Q000473:pathology; D053245:RANK Ligand; D051381:Rats; D053246:Receptor Activator of Nuclear Factor-kappa B; D018123:Receptors, Interleukin / Q000502:physiology; D053722:Receptors, Interleukin-17; D013045:Species Specificity; D013582:Synovial Fluid / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D018501:Antirheumatic Agents; D002352:Carrier Proteins; D016207:Cytokines; C109985:IL17RA protein, human; C491673:Il17ra protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha