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Mammalian target of rapamycin complex 2 (mTORC2) regulates LPS-induced expression of IL-12 and IL-23 in human
Wen-Chi Wei1, Chih-Pin Liu1, Wen-Chin Yang1
1*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.
Abstract:
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.
