Biphasic regulation of the development of murine type II collagen- induced arthritis by interleukin-12: Possible involvement of endogenous interleukin-10 and tumor necrosis factor α

Abstract

Objective. To examine the dose-specific effects of interleukin-12 (IL- 12) on the evolution of murine type II collagen-induced arthritis (CIA). Methods. From day 24 through day 33 following primary immunization, mice received daily intraperitoneal injections of murine recombinant IL-12. Measurements of anticollagen IgG, cytokines, and corticosterone were performed using enzyme-linked immunosorbent assay and radioimmunoassay. Results. CIA mice injected with a low dose of IL-12 (5 ng/day) exhibited accelerated onset and increased severity of arthritis. In contrast, administration of a high dose of IL-12 (500 ng/day) attenuated arthritic inflammation. The low dose of IL-12 induced tumor necrosis factor α (TNFα) production, whereas the high dose induced production of both IL-10 and corticosterone and suppression of anticollagen antibody levels. Administration of neutralizing anti-TNFα and anti-IL-10 antibodies reversed the dose-specific effects of IL-12. Conclusion. IL-12 is an important immunomodulator during the pathogenesis of CIA. It appears to act by regulating humoral and cellular immune responses, as well as by mediating the expression of immunoregulatory cytokines and glucocorticoids.