Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-β-signaling pathways regulates the innate inflammatory response

Huizhi Wang, Jonathan Brown, Zhen Gu, Carlos A. Garcia, Ruqiang Liang, Pascale Alard, Eleonore Beurel, Richard S Jope, Terrance Greenway, Michael Martin

Research output: Contribution to journalArticle

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Abstract

The PI3K pathway and its regulation of mammalian target of rapamycin complex 1 (mTORC1) and glycogen synthase kinase 3 (GSK3) play pivotal roles in controlling inflammation. In this article, we show that mTORC1 and GSK3-β converge and that the capacity of mTORC1 to affect the inflammatory response is due to the inactivation of GSK3-β. Inhibition of mTORC1 attenuated GSK3 phosphorylation and increased its kinase activity. Immunoprecipitation and in vitro kinase assays demonstrated that GSK3-β associated with a downstream target of mTORC1, p85S6K, and phosphorylated GSK3-β. Inhibition of S6K1 abrogated the phosphorylation of GSK3-b while increasing and decreasing the levels of IL-12 and IL-10, respectively, in LPS-stimulated monocytes. In contrast, the direct inhibition of GSK3 attenuated the capacity of S6K1 inhibition to influence the levels of IL-10 and IL-12 produced by LPS-stimulated cells. At the transcriptional level, mTORC1 inhibition reduced the DNA binding of CREB and this effect was reversed by GSK3 inhibition. As a result, mTORC1 inhibition increased the levels of NF-κB p65 associated with CREB-binding protein. Inhibition of NF-κB p65 attenuated rapamycin's ability to influence the levels of pro- or antiinflammatory cytokine production in monocytes stimulated with LPS. These studies identify the molecular mechanism by which mTORC1 affects GSK3 and show that mTORC1 inhibition regulates pro- and anti-inflammatory cytokine production via its capacity to inactivate GSK3.

Original languageEnglish
Pages (from-to)5217-5226
Number of pages10
JournalJournal of Immunology
Volume186
Issue number9
DOIs
StatePublished - May 1 2011
Externally publishedYes

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Glycogen Synthase Kinase 3
Interleukin-12
Interleukin-10
Monocytes
mechanistic target of rapamycin complex 1
Anti-Inflammatory Agents
Phosphotransferases
Phosphorylation
CREB-Binding Protein
Cytokines
Sirolimus
Phosphatidylinositol 3-Kinases
Immunoprecipitation

ASJC Scopus subject areas

  • Immunology

Cite this

Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-β-signaling pathways regulates the innate inflammatory response. / Wang, Huizhi; Brown, Jonathan; Gu, Zhen; Garcia, Carlos A.; Liang, Ruqiang; Alard, Pascale; Beurel, Eleonore; Jope, Richard S; Greenway, Terrance; Martin, Michael.

In: Journal of Immunology, Vol. 186, No. 9, 01.05.2011, p. 5217-5226.

Research output: Contribution to journalArticle

Wang, Huizhi ; Brown, Jonathan ; Gu, Zhen ; Garcia, Carlos A. ; Liang, Ruqiang ; Alard, Pascale ; Beurel, Eleonore ; Jope, Richard S ; Greenway, Terrance ; Martin, Michael. / Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-β-signaling pathways regulates the innate inflammatory response. In: Journal of Immunology. 2011 ; Vol. 186, No. 9. pp. 5217-5226.
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