The role of T-cell interleukin-17 in conducting destructive arthritis: lessons from animal models

Abstract

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.

Figure 1

Schematic overview of interleukin-17 (IL-17) in relation to other key cytokines in the pathogenesis of arthritis. RANKL, receptor activator of NF-κB ligand; TNF, tumor necrosis factor.

Figure 2

Schematic overview of the mechanism of interleukin-17 (IL-17) in bone resorption. The interrelationship of IL-17 with receptor activator of NF-κB ligand (RANKL), IL-1, tumor necrosis factor (TNF) and the modulatory role of IL-4 and osteoprotegerin (OPG) is presented. OC, osteoclast.