Protein kinase C theta plays a fundamental role in different types of chronic colitis.
Protein kinase C theta plays a fundamental role in different types of chronic colitis.
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DOI：
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发表时间：
2008
期刊：
影响因子：
29.4
通讯作者：
Kiyotaka Nagahama;A. Ogaẃa;K. Shirane;Y. Shimomura;K. Sugimoto;A. Mizoguchi
中科院分区：
文献类型：
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作者：
Kiyotaka Nagahama;A. Ogaẃa;K. Shirane;Y. Shimomura;K. Sugimoto;A. Mizoguchi
背景和目的宿主/微生物相互作用失调通过激活有害的获得性免疫反应而诱发结肠炎的发生。 CD4(+) T 细胞的激活主要是通过与免疫突触 (IS) 相关的信号机制诱导的。与 IS 相关的关键分子是蛋白激酶 C (PKC) theta。然而，PKCtheta 在结肠炎发病机制中的作用尚未完全明确。方法 通过产生双 KO 小鼠并利用细胞转移方法，检查 PKCtheta 在不同类型结肠炎（CD45RB 模型、T 细胞受体 [TCR] α 敲除 [KO] 小鼠和白细胞介素 [IL]-2KO 小鼠）发展中获得性免疫反应的作用。结果 PKCtheta 缺陷的幼稚 CD4(+) T 细胞的过继转移未能在免疫缺陷宿主（CD45RB 模型）中诱导 T 辅助细胞 (Th) 1 介导的结肠炎。 TCRalphaKO 小鼠中 Th2 介导的结肠炎的发展也因 PKCtheta 的缺失而受到抑制。在由于T细胞稳态失调而发生结肠炎的IL-2KO小鼠中，CD4(+) T细胞中PKCtheta的缺陷未能诱导严重结肠炎的发生。有趣的是，PKCtheta 的缺失导致结肠记忆 CD4(+) T 细胞的增殖显着减少，但不会导致细胞凋亡。这种增殖受损导致能够产生IL-17的结肠CD4(+) T细胞显着减少。此外，PKCtheta 缺陷会抑制结肠 CD4(+) T 细胞产生 Th2 细胞因子。结论 PKCtheta 在不同类型结肠炎的发展中是一种常见且基本的信号分子，并且可能是治疗炎症性肠病的一个有吸引力的靶点。
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.