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.
Keywords:
NF-κB; Th1; Th17; cytopiloyne.
© Society for Leukocyte Biology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / immunology
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Animals
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Carrier Proteins / antagonists & inhibitors
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Carrier Proteins / immunology
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Cell Differentiation
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Dendritic Cells / cytology
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Dendritic Cells / drug effects
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Dendritic Cells / immunology*
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Gene Expression Regulation
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Glucosides / pharmacology
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Humans
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Interleukin-12 / genetics
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Interleukin-12 / immunology*
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Interleukin-12 Subunit p40 / genetics
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Interleukin-12 Subunit p40 / immunology*
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Lipopolysaccharides / pharmacology*
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Mechanistic Target of Rapamycin Complex 2
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Monocytes / cytology
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Monocytes / drug effects
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Monocytes / immunology
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Multiprotein Complexes / antagonists & inhibitors
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Multiprotein Complexes / genetics
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Multiprotein Complexes / immunology*
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NF-kappa B / genetics
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NF-kappa B / immunology
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Polyynes / pharmacology
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Primary Cell Culture
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Interleukin / genetics
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Receptors, Interleukin / immunology*
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Signal Transduction
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TOR Serine-Threonine Kinases / antagonists & inhibitors
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TOR Serine-Threonine Kinases / genetics
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TOR Serine-Threonine Kinases / immunology*
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Glucosides
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IL23R protein, human
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Interleukin-12 Subunit p40
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Lipopolysaccharides
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MAPKAP1 protein, human
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Multiprotein Complexes
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NF-kappa B
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RICTOR protein, human
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RNA, Small Interfering
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Rapamycin-Insensitive Companion of mTOR Protein
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Receptors, Interleukin
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cytopiloyne
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Interleukin-12
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Polyynes
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MTOR protein, human
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Mechanistic Target of Rapamycin Complex 2
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases