Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells

Masashi Ohtani, Shigenori Nagai, Shuhei Kondo, Shinta Mizuno, Kozue Nakamura, Masanobu Tanabe, Tsutomu Takeuchi, Satoshi Matsuda, Shigeo Koyasu

Research output: Contribution to journalArticle

184 Citations (Scopus)

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 down-stream 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. LiCI, 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.

Original languageEnglish
Pages (from-to)635-643
Number of pages9
JournalBlood
Volume112
Issue number3
DOIs
Publication statusPublished - 2008 Aug 1

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Glycogen Synthase Kinase 3
Sirolimus
Interleukin-12
Dendritic Cells
Lipopolysaccharides
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Th1-Th2 Balance
Interleukin-10
Phosphotransferases
Leishmania major
Lentivirus
Toll-Like Receptors
Chemical activation

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. / Ohtani, Masashi; Nagai, Shigenori; Kondo, Shuhei; Mizuno, Shinta; Nakamura, Kozue; Tanabe, Masanobu; Takeuchi, Tsutomu; Matsuda, Satoshi; Koyasu, Shigeo.

In: Blood, Vol. 112, No. 3, 01.08.2008, p. 635-643.

Research output: Contribution to journalArticle

Ohtani, M, Nagai, S, Kondo, S, Mizuno, S, Nakamura, K, Tanabe, M, Takeuchi, T, Matsuda, S & Koyasu, S 2008, 'Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells', Blood, vol. 112, no. 3, pp. 635-643. https://doi.org/10.1182/blood-2008-02-137430
Ohtani, Masashi ; Nagai, Shigenori ; Kondo, Shuhei ; Mizuno, Shinta ; Nakamura, Kozue ; Tanabe, Masanobu ; Takeuchi, Tsutomu ; Matsuda, Satoshi ; Koyasu, Shigeo. / Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. In: Blood. 2008 ; Vol. 112, No. 3. pp. 635-643.
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