IL-12 Family Cytokines in Inflammation and Bone Erosion of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterised by chronic joint inflammation. The precise aetiology of this autoimmune process remains unclear. Soluble factors produced by infiltrating synovial cells play an important role in driving the inflammatory process that leads to inflammatory cell migration and proliferation in the synovial tissue. These soluble factors consist mainly of cytokines that either promote or suppress inflammation. A number of cytokines have been identified in synovial fluid and the synovial membrane. Cytokines such as TNF, IL-1 and IL-6 stimulate T-cells and induce subsequent cartilage and bone erosion (Kang et al., 2009). Along with IL-18, these cytokines are produced by synovial macrophages and synovial fibroblasts. IL-18 causes joint inflammation and subsequent bone destruction by facilitating T-cell activation and stimulating B-cell production of autoantibodies. Deletion of the IL-18 gene in mice has been shown to result in a significant reduction in the incidence of joint inflammation and bone destruction (Wei et al., 2001). CD4+ T-cells proliferate in inflamed synovial joints through stimulation of IL-15. Inhibition IL-15 results in a significantly lower production of TNF and IL-1. As such, IL-15 blockade abolishes severe joint inflammation in collagen induced-arthritis mouse models (Ruchatz et al., 1998). In the CD4+ T-cell population, Th17 has been demonstrated as a pathogenic T-cell that produces IL-17 to induce neutrophil migration (Shibata et al., 2009). IL-17 is known to stimulate receptor-activator of nuclear factor kappa-B ligand (RANKL) production by osteoblast cells to promote osteoclastogenesis in RA bone erosion (Joosten et al., 2003). Th17 development is governed by TGF, IL-1 and IL-23 (Paradowska-Gorycka et al., 2010; Santarlasci et al., 2009). Higher concentrations of IL-23 (a member of the IL-12 family cytokines) are detected in the serum and synovial fluid of patients with greater severity of RA (Melis et al., 2010). IL-23 can also be produced by osteoblast cells after stimulation with TNF (unpublished data). It is possible that remission of joint inflammation in RA patients can occur spontaneously. The fluctuation in inflammation within the joint results from auto-inhibition through the production of anti-inflammatory cytokines via regulatory T (Treg) cells (Raghavan et al.,