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 alpha

Objective. To examine the dose-specific effects of interleukin-12 (IL-12) o n the evolution of murine type TI collagen-induced arthritis (CU), Methods. From day 24 through day 33 following primary immunization, mice re ceived daily: intraperitoneal injections of murine recombinant IL-12. Measu rements of anticollagen IgG, cytokines, and corticosterone were performed u sing enzyme-linked immunosorbent assay and radioimmunoassay. Results, CIA mice injected with a low dose of IL-12 (5 mg/day) exhibited ac celerated onset and increased severity of arthritis. In contrast, administr ation of a high dose of IL-12 (500 ng/day) attenuated arthritic inflammatio n. The low dose of IL-12 induced tumor necrosis factor alpha (TNF alpha) pr oduction, whereas the high dose induced production of both IL-10 and cortic osterone and suppression of anticollagen antibody levels. Administration of neutralizing anti-TNF alpha and anti-IL-IO antibodies reversed the dose-sp ecific effects of IL-12. Conclusion. IL-12 is an important immunomodulator during the pathogenesis o f CIA, It appears to act by regulating humoral and cellular immune response s, as well as by mediating the expression of immunoregulatory cytokines and glucocorticoids.