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Blood, 1 August 2008, Vol. 112, No. 3, pp. 635-643. Prepublished online as a Blood First Edition Paper on May 20, 2008; DOI 10.1182/blood-2008-02-137430. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-02-137430v1 112/3/635    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Ohtani, M. Articles by Koyasu, S. PubMed PubMed Citation Articles by Ohtani, M. Articles by Koyasu, S. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells Masashi Ohtani1,2, Shigenori Nagai1,2, Shuhei Kondo1, Shinta Mizuno1, Kozue Nakamura1, Masanobu Tanabe3, Tsutomu Takeuchi3, Satoshi Matsuda1,2, and Shigeo Koyasu1,2 1 Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo; 2 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama; and 3 Department of Tropical Medicine and Parasitology, Keio University School of Medicine, Tokyo, Japan 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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