Regulation of Inflammation by Somatostatin via SSTR 2

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DESCRIPTION (provided by applicant): Somatostatin (SOM) decreases inflammation in murine models and human disease. SOM is a cyclic 14 amino acid peptide produced in the mucosa and at sites of inflammation. SOM is made by inflammatory macrophages. SOM may have a critical role regulating inflammation by inhibiting T cell IFN-? release. Macrophage SOM production is induced by LPS, IFN-?, IL 10, TNF-?, PgE2 and cAMP. Murine inflammatory T cells express only one type of SOM receptor, SSTR2. SSTR2 also is expressed at sites of inflammation in patients. SOM-mediated inhibition of IFN-? production requires functional SSTR2. The central hypothesis of this proposal is that the regulation of SOM production and signaling through the SSTIR2 receptor controls Th1 responses in health and disease. SOM may be a particularly important immunomodulator at mucosal surfaces where SOM is plentiful. This proposal has three specific aims. Aim 1 seeks to determine how macrophage production of SOM is regulated at the molecular level. The goal of this aim is to elucidate the pathways used by LPS and IFN-? to induce macrophage SOM expression. Aim 2 seeks to determine how SSTR2 regulates T cell function. This aim will determine if SSTR2 couples to phosphatases and inhibitory signaling factors in Th1 cells to down regulate IFN-? release. Aim 3 seek to determine the in vivo effects of removing SOM-SSTR2 circuitry on inflammation. This aim will use inbred mice that lack SOM or SSTR2 to study the immunoregulatory role of SOM-SSTR2 in three murine models of inflammation. The models are: TNBS colitis, IL 10 deficient colitis, and schistosome egg granulomas.This proposal will study the mechanisms controlling SOM production and regulation of T cell-mediated inflammation. These studies will provide novel insights into the immunoregulation of inflammation at mucosal surfaces rich in endogenous SOM. The results of these studies will provide rationale for novel therapeutic treatment of IBD and other inflammatory diseases.