title: Mammalian target of rapamycin complex 2 (mTORC2) regulates LPS-induced expression of IL-12 and IL-23 in human dendritic cells.
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.
authors: *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.
authors: Wen-Chi
authors: WC
authors: Wei
authors: *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.
authors: Chih-Pin
authors: CP
authors: Liu
authors: *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.
authors: Wen-Chin
authors: WC
authors: Yang
authors: *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.
authors: Lie-Fen
authors: LF
authors: Shyur
authors: *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.
authors: Jyh-Horng
authors: JH
authors: Sheu
authors: *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.
authors: Swey-Shen
authors: SS
authors: Chen
authors: *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 nsyang@gate.sinica.edu.tw.
authors: Ning-Sun
authors: NS
authors: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D005786:Gene Expression Regulation; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000076225:Mechanistic Target of Rapamycin Complex 2; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D053279:Polyynes / Q000494:pharmacology; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D005960:Glucosides; C515500:IL23R protein, human; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; C493277:MAPKAP1 protein, human; D046912:Multiprotein Complexes; D016328:NF-kappa B; C492571:RICTOR protein, human; D034741:RNA, Small Interfering; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D018123:Receptors, Interleukin; C520271:cytopiloyne; D018664:Interleukin-12; D053279:Polyynes; C546842:MTOR protein, human; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: NF-κB; Th1; Th17; cytopiloyne