title: Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells.
abstract: Phosphoinositide 3-kinase (PI3K) negatively regulates Toll-like receptor (TLR)-mediated interleukin-12 (IL-12) expression in dendritic cells (DCs). We show here that 2 signaling pathways downstream of PI3K, mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3 (GSK3), differentially regulate the expression of IL-12 in lipopolysaccharide (LPS)-stimulated DCs. Rapamycin, an inhibitor of mTOR, enhanced IL-12 production in LPS-stimulated DCs, whereas 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 with untreated DCs. LiCl, an inhibitor of GSK3, suppressed a Th1 response on 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.
authors.affiliation: Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Ohtani
authors.forename: Shigenori
authors.initials: S
authors.lastname: Nagai
authors.forename: Shuhei
authors.initials: S
authors.lastname: Kondo
authors.forename: Shinta
authors.initials: S
authors.lastname: Mizuno
authors.forename: Kozue
authors.initials: K
authors.lastname: Nakamura
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tanabe
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takeuchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsuda
authors.forename: Shigeo
authors.initials: S
authors.lastname: Koyasu
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D016753:Interleukin-10 / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011494:Protein Kinases / Q000502:physiology*; D006377:T-Lymphocytes, Helper-Inducer; D058570:TOR Serine-Threonine Kinases
chemical_list: D008070:Lipopolysaccharides; D016753:Interleukin-10; D018664:Interleukin-12; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3