Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient

Objective. To investigate the roles of interleukin-6 (IL-6) in the pathogen esis of rheumatoid arthritis (RA) by studying its effect on murine collagen -induced arthritis (CIA). Methods. IL-6-deficient (IL-6-/-) mice with a genetic background of suscept ibility to CIA were generated by backcrossing them with DBA/1J mice for 8 g enerations. Clinical and immunologic features were compared between these m ice and IL-6 wild-type (IL-6+/+) littermates with CIA. Results. Serum IL-6 levels increased during the development of CIA in IL-6/+ mice. Two prominent peaks were observed. The first was coincident with t he 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 we eks compared with that in IL-6+/+ mice, and the severity of arthritis, as i ndicated by the arthritis score, remained significantly lower in IL-6-/- mi ce during the entire followup period (14 weeks), although all IL-6-/- mice developed definite arthritis as did the IL-6+/+ mice. Histologic severity w as also reduced in IL-6-/- mice. In addition, radiologic changes such as os teopenia and bone erosion were reduced significantly in these animals. Both humoral and cellular responses to type II collagen (CII) in IL-6-/- mice w ere reduced to about half those in IL-6+/+ mice. In addition, enhanced prod uction of IL-4 and IL-10 in response to concanavalin A stimulation was obse rved in IL-6-/- mice. Conclusion. IL-6 plays an important role in the development of CIA, and bot h 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.