Interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17.

OBJECTIVE: The enhanced expression of experimental arthritis in the absence of interferon-gamma (IFNgamma) suggests that IFNgamma suppresses arthritis. Interleukin-17 (IL-17) is a pivotal T cell cytokine in arthritis, and in vitro studies have indicated that IFNgamma suppresses IL-17 production. We undertook this study to test the hypothesis that resistance to collagen-induced arthritis (CIA) in C57BL/6 (B6) mice is regulated by IFNgamma-mediated suppression of IL-17.
METHODS: Wild-type (WT) B6 mice, IFNgamma-knockout (KO) B6 mice, and DBA/1 mice were immunized with type II collagen (CII) in Freund's complete adjuvant (CFA). Lymphocytes from immunized mice were analyzed for cytokine production ex vivo by intracellular staining or restimulation with CII and enzyme-linked immunosorbent assays. In vivo blockade of IL-17 was achieved with an anti-IL-17 monoclonal antibody (mAb).
RESULTS: CII restimulation of T cells from CII/CFA-immunized mice resulted in an approximately 5-fold increase in IL-17 production in IFNgamma-KO B6 mice compared with WT B6 mice. Neutralization of IFNgamma increased IL-17 production in WT B6 mice, and neutralization of IL-4 had a synergistic effect. Interestingly, the prototypical CIA-susceptible strain DBA/1 also demonstrated a high IL-17 and a low IFNgamma cytokine profile compared with WT B6 mice. Administration of the anti-IL-17 mAb attenuated arthritis in DBA/1 mice and almost completely prevented expression of arthritis in IFNgamma-KO B6 mice.
CONCLUSION: These results indicate that sensitivity of IFNgamma-deficient B6 mice to CIA is associated with high IL-17 production and that this cytokine is required for expression of arthritis in this strain.