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

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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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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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, 112(3), 635-643. https://doi.org/10.1182/blood-2008-02-137430