mTORC1 Regulates Flagellin-Induced Inflammatory Response in Macrophages

PLoS One. 2015 May 5;10(5):e0125910. doi: 10.1371/journal.pone.0125910. eCollection 2015.

Abstract

Bacterial flagellin triggers inflammatory responses. Phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) regulate the production of pro- and anti-inflammatory cytokines that are induced by extrinsic antigens, but the function of mTORC1 in flagellin-induced inflammatory response is unknown. The purpose of this study was to examine the role and the mechanism of PI3K/Akt/mTOR pathway in flagellin-induced cytokine expression in mouse macrophages. We observed that flagellin upregulated TNF-α time- and dose-dependently. Flagellin stimulated rapid (<15 min) PI3K/Akt/mTOR phosphorylation that was mediated by TLR5. Inhibition of PI3K with LY294002 and wortmannin, and of mTORC1 with rapamycin decreased flagellin-induced TNF-α and IL-6 expression and cell proliferation. The activation of NF-κB p65 and STAT3 was regulated by mTORC1 via degradation of IκBα and phosphorylation of STAT3 in response to flagellin, respectively. Thus, the PI3K/Akt/mTORC1 pathway regulates the innate immune response to bacterial flagellin. Rapamycin is potential therapy that can regulate host defense against pathogenic infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation / drug effects
  • Cell Survival
  • Chromones / pharmacology
  • Cytokines / metabolism
  • Dose-Response Relationship, Drug
  • Flagellin / metabolism*
  • Flagellin / pharmacology
  • Gene Expression Regulation
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism*
  • MAP Kinase Signaling System / drug effects
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Macrophages, Peritoneal / drug effects
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Morpholines / pharmacology
  • Multiprotein Complexes / metabolism*
  • NF-kappa B / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / metabolism*
  • Toll-Like Receptor 5 / antagonists & inhibitors
  • Toll-Like Receptor 5 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Chromones
  • Cytokines
  • Morpholines
  • Multiprotein Complexes
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • STAT3 Transcription Factor
  • Toll-Like Receptor 5
  • Tumor Necrosis Factor-alpha
  • Flagellin
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases

Grants and funding

This work was supported by a grant from the Natural Sciences Foundation of China (No. 31160469, 31360561), a graduate student research project of Inner Mongolia University, and the Major Projects for New Varieties of Genetically Modified Organisms (No.2014ZX08008-002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.