Functions of IL-17 Family Cytokines in Health and Disease

National Institute Of Allergy And Infectious Diseases

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Abstract

Rheumatoid arthritis (RA) and Systemic Lupus Erythematosus (SLE) are debilitating autoimmune diseases afflicting millions of Americans; they also cause a significant economic burden. Recently both diseases have been associated with aberrant T helper-17 (Th17) responses. IL-17(A), along with the less potent IL-17F, are the signature cytokines of Th17 cells; they are members of the IL-17 cytokine family. Adaptive Th17 immune responses and the IL-17 cytokines they produce play important roles in defense against many extracellular bacteria and fungi, but they have also been implicated in a number of autoimmune diseases, including multiple sclerosis, RA and SLE, as well as in inflammatory diseases, including psoriasis. All IL-17 cytokines signal via an adaptor protein we previously cloned named CIKS. In FY 2011 we reported the functional significance of CIKS in collagen-induced arthritis (CIA), a mouse model of RA. Mice lacking CIKS were effectively protected from disease and more protected than mice lacking only IL-17, indicating contributions from not only IL-17, but also other members of the family to CIA pathology. This provided a proof-of-principle indicating that CIKS is a possible target for therapeutic intervention in RA. In FY 2012 we have explored the role of CIKS and IL-17 in SLE. We have engineered mice lacking CIKS or lacking IL-17 on a lupus-prone background strain, the FcgammaR2b knockout mouse model. Previously it has been suggested that IL-17 cytokines contribute to lupus pathology via effects on autoantibody production. We have now demonstrated that in the FcgammaR2b lupus model IL-17 cytokine signaling via CIKS is critically important for development of lupus nephritis, the most dangerous consequence of developing lupus. . While autoantibodies continued to be generated even in the absence of CIKS, these were largely prevented from causing fatal glomerulonephritis. Loss of CIKS was more protective than loss of IL-17, again suggesting contributions from other IL-17 cytokine family members. These finding provide the first evidence that IL-17 cytokines signaling via CIKS is critical for the development of lupus nephritis and thus constitute a proof-of-principle that IL-17 cytokines and their signaling via CIKS are potential targets of therapeutic intervention in lupus nephritis, a potentially fatal consequence of lupus. In FY 2012 we have also set up mouse models of psoriasis in order to explore the molecular mechanisms underlying IL-17 cytokines-driven pathology in this disease.