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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line
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Cell Proliferation / drug effects
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Cell Survival
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Chromones / pharmacology
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Cytokines / metabolism
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Dose-Response Relationship, Drug
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Flagellin / metabolism*
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Flagellin / pharmacology
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Gene Expression Regulation
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Inflammation / genetics
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Inflammation / immunology
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Inflammation / metabolism*
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MAP Kinase Signaling System / drug effects
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism*
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Macrophages, Peritoneal / drug effects
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Macrophages, Peritoneal / immunology
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Macrophages, Peritoneal / metabolism
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Mechanistic Target of Rapamycin Complex 1
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Mice
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Morpholines / pharmacology
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Multiprotein Complexes / metabolism*
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NF-kappa B / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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STAT3 Transcription Factor / metabolism
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Signal Transduction / drug effects
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TOR Serine-Threonine Kinases / metabolism*
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Toll-Like Receptor 5 / antagonists & inhibitors
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Toll-Like Receptor 5 / metabolism
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Tumor Necrosis Factor-alpha / metabolism
Substances
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Chromones
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Cytokines
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Morpholines
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Multiprotein Complexes
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NF-kappa B
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Phosphoinositide-3 Kinase Inhibitors
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STAT3 Transcription Factor
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Toll-Like Receptor 5
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Tumor Necrosis Factor-alpha
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Flagellin
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins c-akt
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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.