Wei Wen-Chi, Liu Chih-Pin, Yang Wen-Chin, Shyur Lie-Fen, Sheu Jyh-Horng, Chen Swey-Shen, Yang Ning-Sun
*Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC.
*Agricultural Biotechnology Research Center, Academia Sinica, Taiwan, ROC; Department of Diabetes and Metabolic Diseases Research, Department of Immunology, Beckman Research Institute, City of Hope Duarte, California, USA; Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan, ROC; Department of Allergy and Immunology, IgE Therapeutics, Inc., San Diego, California, USA; and Department of Molecular Biology, The Scripps Research Institute, La Jolla, California, USA; Department of Life Science, National Taiwan University, Taipei, Taiwan, ROC; and Department of Life Science, National Central University, Taoyuan County, Taiwan, ROC
J Leukoc Biol. 2015 Jun;97(6):1071-80. doi: 10.1189/jlb.2A0414-206RR. Epub 2015 Apr 15.
IL-12 p40, a common subunit for both IL-12 p70 and IL-23, plays a critical role in the development of Th1 and Th17 cells and autoimmune diseases. Regulation of IL-12 p40 expression is thus considered to be a strategy for developing therapies for Th1- and Th17-mediated autoimmune diseases. The mTOR protein is a subunit mTORC1 and mTORC2. Although mTORC1 has been shown to mediate IL-12 p40 expression in DCs and relevant signaling, the role of mTORC2 in IL-12 p40 expression remains largely unclear. In the present study, we demonstrate that blocking mTORC2 activity using the phytochemical cytopiloyne can specifically inhibit LPS-induced expression of IL-12 p70, IL-23, and IL-12 p40 in human DCs. This regulation by mTORC2 involving Akt activation and the persistent phase of NF-κB activation is further confirmed by siRNA knockdown of Rictor and Sin1 gene expression and the use of alternative inhibition approaches. In terms of IL-12 p40 expression, our findings reveal a new role for the mTORC2 pathway that is antagonistic to that of mTORC1. Our study provides new insight into mTOR regulation of IL-12 p40-mediated Th1 (IFN-γ) and Th17 (IL-17) responses and suggests that the phytochemical cytopiloyne might have useful applications in therapies for Th1 and Th17 cell-mediated inflammatory diseases.
白细胞介素12 p40是白细胞介素12 p70和白细胞介素23的共同亚基，在辅助性T细胞1（Th1）和辅助性T细胞17（Th17）的发育以及自身免疫性疾病中起关键作用。因此，白细胞介素12 p40表达的调控被认为是开发针对Th1和Th17介导的自身免疫性疾病治疗方法的一种策略。哺乳动物雷帕霉素靶蛋白（mTOR）是mTOR复合物1（mTORC1）和mTOR复合物2（mTORC2）的一个亚基。尽管mTORC1已被证明可介导树突状细胞（DC）中白细胞介素12 p40的表达及相关信号传导，但mTORC2在白细胞介素12 p40表达中的作用仍不清楚。在本研究中，我们证明使用植物化学物质细胞多炔阻断mTORC2活性可特异性抑制人DC中脂多糖（LPS）诱导的白细胞介素12 p70、白细胞介素23和白细胞介素12 p40的表达。雷帕霉素靶蛋白相互作用蛋白（Rictor）和应激激活蛋白激酶相互作用蛋白1（Sin1）基因表达的小干扰RNA（siRNA）敲低以及使用其他抑制方法进一步证实了mTORC2通过涉及蛋白激酶B（Akt）激活和核因子κB（NF-κB）激活持续阶段的这种调控。就白细胞介素12 p40表达而言，我们的研究结果揭示了mTORC2途径的一个新作用，该作用与mTORC1的作用相反。我们的研究为mTOR对白细胞介素12 p40介导的Th1（干扰素-γ）和Th17（白细胞介素-17）反应的调控提供了新见解，并表明植物化学物质细胞多炔可能在Th1和Th17细胞介导的炎症性疾病治疗中具有有用的应用价值。
