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Mammalian target of rapamycin complex 2 (mTORC2) regulates LPS‐induced expression of IL‐12 and IL‐23 in human dendritic cells

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.