To investigate the roles of interleukin‐6 (IL‐6) in the pathogenesis of rheumatoid arthritis (RA) by studying its effect on murine collagen‐induced arthritis (CIA).

IL‐6–deficient (IL‐6−/−) mice with a genetic background of susceptibility to CIA were generated by backcrossing them with DBA/1J mice for 8 generations. Clinical and immunologic features were compared between these mice and IL‐6 wild‐type (IL‐6+/+) littermates with CIA.

Serum IL‐6 levels increased during the development of CIA in IL‐6+/+ mice. Two prominent peaks were observed. The first was coincident with the onset of arthritis, and the second one was observed during exacerbation of the disease. The onset of arthritis in IL‐6−/− mice was delayed for 2 weeks compared with that in IL‐6+/+ mice, and the severity of arthritis, as indicated by the arthritis score, remained significantly lower in IL‐6−/− mice during the entire followup period (14 weeks), although all IL‐6−/− mice developed definite arthritis as did the IL‐6+/+ mice. Histologic severity was also reduced in IL‐6−/− mice. In addition, radiologic changes such as osteopenia and bone erosion were reduced significantly in these animals. Both humoral and cellular responses to type II collagen (CII) in IL‐6−/− mice were reduced to about half those in IL‐6+/+ mice. In addition, enhanced production of IL‐4 and IL‐10 in response to concanavalin A stimulation was observed in IL‐6−/− mice.

IL‐6 plays an important role in the development of CIA, and both suppression of specific immune responses to CII and a tendency to a shift toward a Th2 cytokine profile might contribute in part to the attenuation of CIA in IL‐6−/− mice. These findings suggest that blockade of IL‐6 might be beneficial in the treatment of RA.