J. Exp. Med., Volume 187, Number 4, February 16, 1998 461-468

Interleukin 6 Is Required for the Development of Collagen-induced Arthritis

By Tonino Alonzi,^* Elena Fattori,^* Domenico Lazzaro,^* Patrizia Costa,^* Lesley Probert, George Kollias, Fabrizio De Benedetti,^§ Valeria Poli,^* and Gennaro Ciliberto^*

From the ^* Istituto Ricerche di Biologia Molecolare P.  Angeletti, 00040 Pomezia, Rome, Italy; the  Department of Molecular Genetics, Hellenic Pasteur Institute, 115 21 Athens, Greece; and the ^§ Clinica Pediatrica, Universita' degli Studi di Pavia, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, 27100 Pavia, Italy

Interleukin-6 (IL-6) is overproduced in the joints of patients with rheumatoid 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 development and clinical manifestations of this disease. In this study we have analysed the effect of ablating cytokine production in two mouse models of arthritis: collagen-induced arthritis (CIA) in DBA/1J mice and the inflammatory polyarthritis of tumor necrosis factor  (TNF-) transgenic mice. IL-6 was ablated by intercrossing an IL-6 null mutation into both arthritis-susceptible genetic backgrounds and disease development was monitored by measuring clinical, histological, and biochemical parameters. Two opposite responses were observed; while arthritis in TNF- transgenic mice was not affected by inactivation of the IL-6 gene, DBA/1J, IL-6^/ mice were completely protected from CIA, accompanied by a reduced antibody response to type II collagen and the absence of inflammatory cells and tissue damage in knee joints. These results are discussed in the light of the present knowledge of cytokine networks in chronic inflammatory disorders and suggest that IL-6 receptor antagonists might be beneficial for the treatment of RA.

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