IFN-γ Regulates the Requirement for IL-17 in Proteoglycan-Induced Arthritis

Abstract

The contribution of the proinflammatory cytokines IFN-γ and IL-17 to the pathogenesis of experimental arthritis is controversial. In proteoglycan (PG)-induced arthritis (PGIA), severe arthritis is dependent on the production of IFN-γ, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-γ are secreted, disease is exacerbated in IFN-γ or IFN-γ receptor-deficient mice due to the ability of IFN-γ to suppress IL-17 expression. In the current study, we investigated the effect of IFN-γ on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-γ−/− mice, despite reduction in arthritis, the PG-specific CD4+ T cell IL-17 response was significantly increased. Elevated IL-17 contributed to development of arthritis, as disease in IFN-γ/IL-17−/− was significantly reduced in comparison with either IFN-γ−/− or IL-17−/− mice. A contribution of IFN-γ and IL-17 to the development of arthritis was also identified in T-bet−/− mice. PG-specific CD4+ T cells from T-bet−/− mice produced reduced IFN-γ and elevated concentrations of IL-17. Both IFN-γ and IL-17 contribute to arthritis, as T-bet−/− mice lacking IL-17 (T-bet/IL-17−/−) were resistant, whereas wild-type, T-bet−/−, and IL-17−/− mice were susceptible to PGIA. T cell proliferation and autoantibody production did not correlate with development of disease; however, expression of cytokines and chemokines in joint tissues demonstrate that IFN-γ and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-γ and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-γ response that regulates the contribution of each of these Th effector cytokines to disease.