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 ?

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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.