SEARCH:   Advanced

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 (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 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ohtani, M. Articles by Koyasu, S. Search for Related Content PubMed PubMed Citation Articles by Ohtani, M. Articles by Koyasu, S. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 4, 2008 Accepted April 9, 2008 mTOR and GSK3 differentially regulate LPS-induced IL-12 production in dendritic cells Masashi Ohtani, Shigenori Nagai, Shuhei Kondo, Shinta Mizuno, Kozue Nakamura, Masanobu Tanabe, Tsutomu Takeuchi, Satoshi Matsuda, and Shigeo Koyasu* Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan Department of Tropical Medicine and Parasitology, Keio University School of Medicine, Tokyo, Japan Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama, Japan * Corresponding author; email: koyasu{at}sc.itc.keio.ac.jp. 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Escribano, C. Delgado-Martin, and J. L. Rodriguez-Fernandez CCR7-Dependent Stimulation of Survival in Dendritic Cells Involves Inhibition of GSK3{beta} J. Immunol., November 15, 2009; 183(10): 6282 - 6295. [Abstract] [Full Text] [PDF] E. Lorne, X. Zhao, J. W. Zmijewski, G. Liu, Y.-J. Park, Y. Tsuruta, and E. Abraham Participation of Mammalian Target of Rapamycin Complex 1 in Toll-Like Receptor 2- and 4-Induced Neutrophil Activation and Acute Lung Injury Am. J. Respir. Cell Mol. Biol., August 1, 2009; 41(2): 237 - 245. [Abstract] [Full Text] [PDF] J.-O Jin, H.-Y. Park, Q. Xu, J.-I. Park, T. Zvyagintseva, V. A. Stonik, and J.-Y. Kwak Ligand of scavenger receptor class A indirectly induces maturation of human blood dendritic cells via production of tumor necrosis factor-{alpha} Blood, June 4, 2009; 113(23): 5839 - 5847. [Abstract] [Full Text] [PDF] M. R. Janes and D. A. Fruman Immune Regulation by Rapamycin: Moving Beyond T Cells Sci. Signal., April 21, 2009; 2(67): pe25 - pe25. [Abstract] [Full Text] [PDF]

	Copyright © 2008 by American Society of Hematology         Online ISSN: 1528-0020