mTOR and GSK3 differentially regulate LPS-induced IL-12 production in dendritic cells

Phosphoinositide 3-kinase (PI3K) negatively regulates Toll-like receptor (TLR)-mediated IL-12 expression in dendritic cells (DCs). We show here that two signaling pathways downstream of PI3K, mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 (GSK3), differentially regulate the expression of IL-12 in LPS-stimulated DCs. Rapamycin, an inhibitor of mTOR, enhanced IL-12 production in LPS-stimulated DCs, while the activation of mTOR by lentivirus-mediated transduction of a constitutively active form of Rheb suppressed the production of IL-12. The inhibition of protein secretion or deletion of IL-10 cancelled the effect of rapamycin, indicating that mTOR regulates IL-12 expression through an autocrine action of IL-10. In contrast, GSK3 positively regulates IL-12 production through an IL-10-independent pathway. Rapamycin-treated DCs enhanced Th1 induction in vitro compared to untreated DCs. LiCl, an inhibitor of GSK3, suppressed a Th1 response upon Leishmania major infection in vivo. These results suggest that mTOR and GSK3 pathways regulate the Th1/Th2 balance though the regulation of IL-12 expression in DCs. The signaling pathway downstream of PI3K would be a good target to modulate the Th1/Th2 balance in immune responses in vivo. For personal use only. on August 31, 2017. by guest www.bloodjournal.org From