Positive and Negative Roles of IL-6, STAT3, and SOCS3 in Inflammatory Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of multiple joints, resulting in mononuclear cell infiltration, development of pannus, progressive cartilage destruction and bone erosion. Although the cause of RA remains unknown, it has been suggested that cytokines, especially proinflammatory cytokines such as tumor necrosis factor α(TNF-α), interleukin (IL)-1, and IL-6 derived from activated synovial cells, play a pivotal role in the pathology of the disease (Feldmann, Brennan, and Maini 1996a,b). Among these cytokines, TNF-α has been most extensively investigated as a target in the efforts to treat RA. Anti-TNF-α mAbs markedly ameliorate joint involvement in the majority of patients with RA (Elliott, Maini, Feldmann, et al. 1994a,b). It is well known that IL-6 is one of a major target gene of TNF-α. IL-6 has been proposed to contribute to the development of arthritis; IL-6 induces proliferation of synovial fibroblastic cells (Mihara, Moriya, Kishimoto, et al. 1995) and formation of osteoclasts, in association with soluble IL-6 receptors (Tamura, Udagawa, Takahashi, et al. 1993). Involvement of IL-6 in RA is also suggested by recent reports of IL-6-gene-disrupted mice that were resistant to antigen-induced arthritis (AIA) (Boe, Baiocchi, Carbonatto, et al. 1999; Ohshima, Saeki, Mima, et al. 1998) and collagen-induced arthritis (CIA) (Alonzi, Fattori, Lazzaro, et al. 1998). Therefore, IL-6 could be another therapeutic target of RA. Recently, anti-IL6 receptor antibodies have been successfully trialed as a therapy for RA patients (Yoshizaki, Nishimoto, Mihara, et al. 1998). However, the mechanism of suppression of RA by anti-IL-6 therapy has not been fully understood. We investigated the role of IL-6 and its signal regulator, SOCS3 on inflammatory arthritis and osteoclastgenesis using mouse models.