IFN-gamma regulates the requirement for IL-17 in proteoglycan-induced arthritis.

The contribution of the proinflammatory cytokines IFN-gamma 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-gamma, whereas IL-17 is dispensable. In collagen-induced arthritis and Ag-induced arthritis, although high levels of IFN-gamma are secreted, disease is exacerbated in IFN-gamma or IFN-gamma receptor-deficient mice due to the ability of IFN-gamma to suppress IL-17 expression. In the current study, we investigated the effect of IFN-gamma on the IL-17 response and its consequences in PGIA. In PG-immunized IFN-gamma(-/-) 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-gamma/IL-17(-/-) was significantly reduced in comparison with either IFN-gamma(-/-) or IL-17(-/-) mice. A contribution of IFN-gamma 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-gamma and elevated concentrations of IL-17. Both IFN-gamma 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-gamma and IL-17 cooperatively contribute to inflammation. These results demonstrate that both IFN-gamma and IL-17 have the potential to induce PGIA, but it is the strength of the IFN-gamma response that regulates the contribution of each of these Th effector cytokines to disease.