INTERLEUKIN-6 IS REQUIRED FOR THE DEVELOPMENT OF COLLAGEN-INDUCED ARTHRITIS

Interleukin-6 (IL-6) is overproduced in the joints of patients with rh eumatoid arthritis (RA) and, based on its multiple stimulatory effects on cells of the immune system and on vascular endothelia, osteoclasts , and synovial fibroblasts, is believed to participate in the developm ent and clinical manifestations of this disease. In this study we have analysed the effect of ablating cytokine production in two mouse mode ls of arthritis: collagen-induced arthritis (CIA) in DBA/1J mice and t he inflammatory polyarthritis of tumor necrosis factor alpha (TNF-alph a) transgenic mice. IL-6 was ablated by intercrossing an IL-6 null mut ation into both arthritis-susceptible genetic backgrounds and disease development was monitored by measuring clinical, histological, and bio chemical parameters. Two opposite responses were observed; while arthr itis in TNF-alpha transgenic mice was not affected by inactivation of the IL-6 gene, DBA/1J, IL-6(-/-) mice were completely protected from C IA, accompanied by a reduced antibody response to type II collagen and the absence of inflammatory cells and tissue damage in knee joints. T hese results are discussed in the light of the present knowledge of cy tokine networks in chronic inflammatory disorders and suggest that IL- 6 receptor antagonists might be beneficial for the treatment of RA.