Interleukin-17 is a recently identified cytokine, which is secreted by activated lymphocytes. IL-17 may be involved in inflammatory processes because it is able to activate NF-kappaB with the subsequent stimulation of inflammatory cytokine expression. We have cloned the human IL-17 receptor from a human small intestinal cDNA library. In this effort we observed four variants of the human IL-17 receptor including a potential soluble IL-17 receptor. Initial experiments demonstrate that rodent and human intestinal epithelial cells express functional IL-17 receptors. The biological responses of intestinal epithelial cells to IL-17 stimulation include the regulation of transepithelial electrical resistance and the TRAF6 dependent activation of NF-kappaB with the subsequent induction of chemokine mRNA expression. However, the signal transduction mediators interacting with the IL-17 receptor upon IL-17 binding are unknown. Furthermore, the functionally significant motifs in the cytoplasmic region and the signal transducer of the mouse and human IL-17 receptors have not been identified. The overall hypothesis is that the variants of the human IL-17 receptor may regulate separate and distinct cellular responses in intestinal epithelial cells. The overall goal of this study is to characterize the biologic function of the human IL-17 receptor and the signal transduction and transcriptional activation events mediating these functions. The purpose of our experiments will be to provide an increased understanding of the signal transduction of IL-17 ligand-receptor system and its role in regulation of human intestinal epithelial cell function.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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Hamilton, Frank A
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Massachusetts General Hospital
United States
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