IL-25 is a member of the IL-17 family of cytokines. IL-17 is the signature cytokine of T helper type 17 (Th17) cells, and the Th17/IL-17 axis has been implicated not only in defense of certain pathogens but also in the pathology associated with a number of inflammatory and auto-immune diseases;these diseases include rheumatoid arthritis, lupus and multiple sclerosis. By contrast, IL-25 has been associated not with Th17 but instead with Th2-mediated responses, e.g. in defense of helminthes. But like IL-17, IL-25 has also been implicated in inflammatory diseases, specifically in allergic asthma. We have previously cloned an adaptor protein named CIKS (a.k.a. Act1) which contains a domain shared with members of the IL-17 receptor family. In FY 2009 we generated CIKS deficient mice and demonstrated that CIKS is required for IL-17 signaling, in agreement with findings by others. Specifically we generated primary mouse embryo fibroblasts to show that IL-17 induced the expression of many genes in wild-type fibroblasts but not in CIKS-deficient ones. The induced genes include chemokines, cytokines, antimicrobial agents and transcription factors. Although the receptor for IL-25 (IL-17RB) is related to the receptor for IL-17 (IL-17RA), it remained to be determined whether CIKS is required for signaling via this cytokine;this task was complicated by the fact that IL-25 target cells had not been clearly identified. In FY 2009 we have determined that CIKS is in fact necessary to mediate the effects of IL-25, as determined with in vivo upon administration of this cytokine into lungs. When administered to wild-type mice in this fashion, IL-25 caused a severe allergic asthma-like inflammation of lungs, including the induction of a Th2-like cytokine profile. By contrast, when administered to mice deficient in CIKS, IL-25 failed to elicit any of the pathologies associated with allergic asthma. We also demonstrated that IL-25 target cells could be found amongst the population of alveolar macrophage-like cells.

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1
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2009
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$1,114,332
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Das, Nitin A; Carpenter, Andrea J; Yoshida, Tadashi et al. (2018) TRAF3IP2 mediates TWEAK/TWEAKR-induced pro-fibrotic responses in cultured cardiac fibroblasts and the heart. J Mol Cell Cardiol 121:107-123
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