Endogenous IL-6 is Needed to Sustain an Efficient Antigen-Specific IL-17 Response in Experimental Autoimmune Uveitis (EAU)

Abstract

Purpose:: We examined the role of IL-6, a multifunctional cytokine involved in regulation of the immune response, in the pathogenesis of experimental autoimmune uveitis (EAU) with particular emphasis on the effect of IL-6 on production of the proinflammatory cytokine IL-17.

Methods:: EAU was induced in IL-6 deficient mice (IL-6 KO) and their C57BL/6 wild-type counterparts by immunization with interphotoreceptor retinoid-binding protein (IRBP) in complete Freund's adjuvant (CFA). EAU development was evaluated by fundus examination and confirmed by histology in eyes collected 21 days after immunization. Immunological responses were examined by delayed type hypersensitivity (DTH), lymphocyte proliferation and cytokine production to IRBP or anti-CD3 in culture by ELISA and by intracellular cytokine staining.

Results:: IL-6 deficient mice were completely resistant to EAU and had significantly reduced DTH and proliferation responses to in vitro recall with IRBP compared to their wild type counterparts. Notably, there was a considerable decrease in production of IL-17 by IL-6 KO mice under these conditions. However, when naive splenocytes were stimulated in vitro with anti-CD3 to mimic a primary response, there was no reduction in the ability of IL-6 KO splenocytes to produce IL-17 as compared to wild-type controls.

Conclusions:: Our results in the EAU model suggest that although initial production of IL-17 is not dependent on endogenous IL-6, this cytokine plays an important role in inducing and sustaining the IL-17 memory and recall responses. The relationship between IL-6 and IL-17 production appears complex and could depend in part on the T cell maturation stage. We are currently investigating also the possibility of IL-17 production by non-T cells.

Keywords: autoimmune disease • cytokines/chemokines • uveitis-clinical/animal model