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  • Title: Protein kinase C theta plays a fundamental role in different types of chronic colitis.
    Author: Nagahama K, Ogawa A, Shirane K, Shimomura Y, Sugimoto K, Mizoguchi A.
    Journal: Gastroenterology; 2008 Feb; 134(2):459-69. PubMed ID: 18155708.
    Abstract:
    BACKGROUND & AIMS: Dysregulated host/microbial interactions induce the development of colitis by activating deleterious acquired immune responses. Activation of CD4(+) T cells is mainly induced through signaling machinery associated with immunologic synapse (IS). A key molecule associated with the IS is protein kinase C (PKC) theta. However, the role of PKCtheta in the pathogenesis of colitis has not fully been defined. METHODS: The role of PKCtheta for the acquired-immune responses involved in the development of different types of colitis (CD45RB model, T-cell receptor [TCR] alpha knockout [KO] mice and interleukin [IL]-2KO mice) was examined by generating double KO mice and by utilizing cell transfer approaches. RESULTS: Adoptive transfer of PKCtheta-deficient naïve CD4(+) T cells failed to induce T helper cell (Th) 1-mediated colitis in the immune-deficient host (CD45RB model). Development of Th2-mediated colitis in TCRalphaKO mice was also inhibited by the absence of PKCtheta. In IL-2KO mice, which develop colitis because of dysregulated T-cell homeostasis, deficiency of PKCtheta in CD4(+) T cells failed to induce the development of severe colitis. Interestingly, absence of PKCtheta led to a remarkable decrease in the proliferation, but not apoptosis, of colonic memory CD4(+) T cells. This impaired proliferation resulted in a marked decrease in the colonic CD4(+) T cells that are capable of producing IL-17. In addition, deficiency of PKCtheta inhibited the production of Th2 cytokines by colonic CD4(+) T cells. CONCLUSIONS: PKCtheta serves as a common and fundamental signaling molecule in the development of different types of colitis and may represent an attractive target for treating inflammatory bowel disease.
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