Granulomatous inflammation is characteristic of many diseases like Crohn's disease, sarcoidosis and primary biliary cirrhosis. Granulomas are focal collections of inflammatory cells, tightly regulated by T cells. In turn, other inflammatory cells types regulate granuloma T cells. Diseases like IBD develop when there is disruption of this cross regulatory circuitry. Much of this regulatory circuitry proceeds through release of neurokines and other lymphokines. Somatostatin (SOM) is one such neurokine that alters lymphocyte responses. Granuloma macrophages secrete SOM. Murine granuloma T cells display SOM receptors as do cells in human granulomas. Five distinct SOM receptors (SSTR) are cloned, sequenced, and characterized. Our current evidence indicates that SSTR2 is the only SOM receptor expressed on granuloma T cells. In addition, granuloma cells express both isoforms of SSTR2. SOM inhibits interferon- gamma (IFN-gamma) release from granuloma T cells. SOM may prove to be an important regulator of chronic inflammation, since IFN-gamma is a pivotal cytokine that regulates many inflammatory cell types. Therefore, to further elucidate the importance of SSTR2 in inflammation, this project will pursue these four hypotheses: 1.) SOM regulates IFN-gamma release from granuloma T cells through interaction with SSTR2, 2.) SSTR2 expression is regulated by T cell activation, 3) The two isoforms of SSTR2 differ in ability to inhibit IFN-gamma release, 4) SOM controls granulomatous responses in vivo by interaction with SSTR2. Murine schistosomiasis provides a well defined natural model system to study granulomas in the intestines and liver. Granulomas in murine schistosomiasis express SOM, SSTR2 and other aspects of the SOM circuit. Thus, we will use cells isolated from these granulomas to achieve the following aims:
Aim 1 : Determine if SOM interacts directly with T cell SSTR2 to regulate IFN-gamma release without the interposed participation of another cell type using receptor blocking antibody, specific agonists, flow cytometry and cloned T cells with abrogated SSTR2 display.
Aim 2 : Determine if T cell activation affects SSTR2 mRNA and protein synthesis, and SSTR2 phosphorylation, and using quantitative RT-PCR, nuclear run-off analysis, flow cytometry, western blotting and immunoprecipitation.
Aim 3 : Determine if the two isoforms of SSTR2 are differentially regulated and have different capacity to inhibit T cell IFN-gamma release using isoform specific quantitative RT-PCR and immunoprecipitation, and selective transfection of the isoforms.
Aim 4 : Determine if intralesional SOM interacts with SSTR2 to regulate granulomas in vivo using SSTR2 blocking antibodies and transgenic mice with selectively impaired T cell SSTR2 display. Our hope is that these discoveries will lead to new therapies for IBD.
| Elliott, David E; Weinstock, Joel V (2009) Helminthic therapy: using worms to treat immune-mediated disease. Adv Exp Med Biol 666:157-66 |
| Elliott, David E; Summers, Robert W; Weinstock, Joel V (2007) Helminths as governors of immune-mediated inflammation. Int J Parasitol 37:457-64 |
| Arsenescu, Razvan; Blum, Arthur M; Metwali, Ahmed et al. (2005) IL-12 induction of mRNA encoding substance P in murine macrophages from the spleen and sites of inflammation. J Immunol 174:3906-11 |
| Elliott, David E; Summers, Robert W; Weinstock, Joel V (2005) Helminths and the modulation of mucosal inflammation. Curr Opin Gastroenterol 21:51-8 |
| Weinstock, Joel V (2004) The role of substance P, hemokinin and their receptor in governing mucosal inflammation and granulomatous responses. Front Biosci 9:1936-43 |
| Blum, Arthur M; Metwali, Ahmed; Elliott, David E et al. (2004) CD4+ T cells from IL-10-deficient mice transfer susceptibility to NSAID-induced Rag colitis. Am J Physiol Gastrointest Liver Physiol 287:G320-5 |
| Weinstock, J V; Summers, R; Elliott, D E (2004) Helminths and harmony. Gut 53:7-9 |
| Sandor, Matyas; Weinstock, Joel V; Wynn, Thomas A (2003) Granulomas in schistosome and mycobacterial infections: a model of local immune responses. Trends Immunol 24:44-52 |
| Weinstock, Joel V; Blum, Arthur; Metwali, Ahmed et al. (2003) IL-18 and IL-12 signal through the NF-kappa B pathway to induce NK-1R expression on T cells. J Immunol 170:5003-7 |
| Blum, Arthur M; Metwali, Ahmed; Elliott, David E et al. (2003) T cell substance P receptor governs antigen-elicited IFN-gamma production. Am J Physiol Gastrointest Liver Physiol 284:G197-204 |
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