mTORC1 Regulates Flagellin-Induced Inflammatory Response in Macrophages

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...

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Veröffentlicht in:PloS one 2015-05, Vol.10 (5), p.e0125910-e0125910
Hauptverfasser: Bao, Wenlei, Wang, Yanfeng, Fu, Yuting, Jia, Xiaoyang, Li, Jiaxin, Vangan, Nyamtsengel, Bao, Lili, Hao, Huifang, Wang, Zhigang
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container_title PloS one
container_volume 10
creator Bao, Wenlei
Wang, Yanfeng
Fu, Yuting
Jia, Xiaoyang
Li, Jiaxin
Vangan, Nyamtsengel
Bao, Lili
Hao, Huifang
Wang, Zhigang
description 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 (
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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 (&lt;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. 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This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Bao et al 2015 Bao et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-3ff8afe469247317bcae24e8ca88d4bc8853b4b4ab2a46e2852c038948587b993</citedby><cites>FETCH-LOGICAL-c692t-3ff8afe469247317bcae24e8ca88d4bc8853b4b4ab2a46e2852c038948587b993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420466/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420466/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79472,79473</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25942007$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Cheng, Jin Q.</contributor><creatorcontrib>Bao, Wenlei</creatorcontrib><creatorcontrib>Wang, Yanfeng</creatorcontrib><creatorcontrib>Fu, Yuting</creatorcontrib><creatorcontrib>Jia, Xiaoyang</creatorcontrib><creatorcontrib>Li, Jiaxin</creatorcontrib><creatorcontrib>Vangan, Nyamtsengel</creatorcontrib><creatorcontrib>Bao, Lili</creatorcontrib><creatorcontrib>Hao, Huifang</creatorcontrib><creatorcontrib>Wang, Zhigang</creatorcontrib><title>mTORC1 Regulates Flagellin-Induced Inflammatory Response in Macrophages</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>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 (&lt;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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Antigens</subject><subject>Apoptosis</subject><subject>Bacteria</subject><subject>Bacterial proteins</subject><subject>Biodegradation</subject><subject>Cancer</subject><subject>Cell activation</subject><subject>Cell culture</subject><subject>Cell growth</subject><subject>Cell Line</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cell Survival</subject><subject>Cellular control mechanisms</subject><subject>Cellular signal transduction</subject><subject>Chromones - pharmacology</subject><subject>Cytokines</subject><subject>Cytokines - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Flagellin</subject><subject>Flagellin - metabolism</subject><subject>Flagellin - pharmacology</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Health aspects</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunoglobulins</subject><subject>Inflammation</subject><subject>Inflammation - genetics</subject><subject>Inflammation - immunology</subject><subject>Inflammation - metabolism</subject><subject>Inflammatory response</subject><subject>Innate immunity</subject><subject>Interleukin 6</subject><subject>Kinases</subject><subject>Life sciences</subject><subject>Macrophages</subject><subject>Macrophages - drug effects</subject><subject>Macrophages - immunology</subject><subject>Macrophages - metabolism</subject><subject>Macrophages, Peritoneal - drug effects</subject><subject>Macrophages, Peritoneal - immunology</subject><subject>Macrophages, Peritoneal - metabolism</subject><subject>Mammals</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Mechanistic Target of Rapamycin Complex 1</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Morpholines - pharmacology</subject><subject>Multiprotein Complexes - metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Pattern recognition</subject><subject>Penicillin</subject><subject>Phosphatidylinositol 3-Kinases - antagonists &amp; inhibitors</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Rapamycin</subject><subject>Signal Transduction - drug effects</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>TLR5 protein</subject><subject>Toll-Like Receptor 5 - antagonists &amp; inhibitors</subject><subject>Toll-Like Receptor 5 - metabolism</subject><subject>Toll-like receptors</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><subject>Viral infections</subject><subject>Wortmannin</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl9v0zAUxSMEYqPwDRBUQkLw0OJ_iZ0XpKliI9JQpTJ4tRznJk3lxF2cIPbtuaXZ1KA9oDw4tn_3XPv4RNFrSpaUS_pp54euNW659y0sCWVxSsmT6JymnC0SRvjTk_-z6EUIO0JirpLkeXSGsGCEyPPoqrlZb1Z0voFqcKaHML90pgLn6naRtcVgoZhnbelM05jed3cIBuwYYF6382_Gdn6_RT68jJ6VxgV4NY6z6Mfll5vV18X1-ipbXVwvbJKyfsHLUpkSBE6E5FTm1gAToKxRqhC5VSrmuciFyZkRCTAVM0u4SoWKlczTlM-it0fdvfNBjx4ETROppGREUiSyI1F4s9P7rm5Md6e9qfXfBd9V2nR9bR3oVBCRU5lwS0AUClKZQ1nGseB5ikYVqPV57DbkDRQW2r4zbiI63Wnrra78Ly3QXpEkKPBhFOj87QCh100dLNprWvDD4dyKUCU5Y4i--wd9_HYjVRm8QN2WHvvag6i-EJzgi8do7CxaPkLhV0BTWwxMWeP6pODjpACZHn73lRlC0Nn3zf-z659T9v0JuwXj-m3wbuhrzNAUFEcQExVCB-WDyZToQ97v3dCHvOsx71j25vSBHoruA87_AFlt-M8</recordid><startdate>20150505</startdate><enddate>20150505</enddate><creator>Bao, Wenlei</creator><creator>Wang, Yanfeng</creator><creator>Fu, Yuting</creator><creator>Jia, Xiaoyang</creator><creator>Li, Jiaxin</creator><creator>Vangan, Nyamtsengel</creator><creator>Bao, Lili</creator><creator>Hao, Huifang</creator><creator>Wang, Zhigang</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150505</creationdate><title>mTORC1 Regulates Flagellin-Induced Inflammatory Response in Macrophages</title><author>Bao, Wenlei ; Wang, Yanfeng ; Fu, Yuting ; Jia, Xiaoyang ; Li, Jiaxin ; Vangan, Nyamtsengel ; Bao, Lili ; Hao, Huifang ; Wang, Zhigang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-3ff8afe469247317bcae24e8ca88d4bc8853b4b4ab2a46e2852c038948587b993</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Antigens</topic><topic>Apoptosis</topic><topic>Bacteria</topic><topic>Bacterial proteins</topic><topic>Biodegradation</topic><topic>Cancer</topic><topic>Cell activation</topic><topic>Cell culture</topic><topic>Cell growth</topic><topic>Cell Line</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cell Survival</topic><topic>Cellular control mechanisms</topic><topic>Cellular signal transduction</topic><topic>Chromones - pharmacology</topic><topic>Cytokines</topic><topic>Cytokines - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Flagellin</topic><topic>Flagellin - metabolism</topic><topic>Flagellin - pharmacology</topic><topic>Gene expression</topic><topic>Gene Expression Regulation</topic><topic>Health aspects</topic><topic>Immune response</topic><topic>Immune system</topic><topic>Immunoglobulins</topic><topic>Inflammation</topic><topic>Inflammation - genetics</topic><topic>Inflammation - immunology</topic><topic>Inflammation - metabolism</topic><topic>Inflammatory response</topic><topic>Innate immunity</topic><topic>Interleukin 6</topic><topic>Kinases</topic><topic>Life sciences</topic><topic>Macrophages</topic><topic>Macrophages - drug effects</topic><topic>Macrophages - immunology</topic><topic>Macrophages - metabolism</topic><topic>Macrophages, Peritoneal - drug effects</topic><topic>Macrophages, Peritoneal - immunology</topic><topic>Macrophages, Peritoneal - metabolism</topic><topic>Mammals</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Mechanistic Target of Rapamycin Complex 1</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Morpholines - pharmacology</topic><topic>Multiprotein Complexes - metabolism</topic><topic>NF-kappa B - metabolism</topic><topic>NF-κB protein</topic><topic>Pattern recognition</topic><topic>Penicillin</topic><topic>Phosphatidylinositol 3-Kinases - antagonists &amp; 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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 (&lt;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. 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identifier ISSN: 1932-6203
ispartof PloS one, 2015-05, Vol.10 (5), p.e0125910-e0125910
issn 1932-6203
1932-6203
language eng
recordid cdi_plos_journals_1678772071
source MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry
subjects 1-Phosphatidylinositol 3-kinase
AKT protein
Animals
Antigens
Apoptosis
Bacteria
Bacterial proteins
Biodegradation
Cancer
Cell activation
Cell culture
Cell growth
Cell Line
Cell proliferation
Cell Proliferation - drug effects
Cell Survival
Cellular control mechanisms
Cellular signal transduction
Chromones - pharmacology
Cytokines
Cytokines - metabolism
Dose-Response Relationship, Drug
Flagellin
Flagellin - metabolism
Flagellin - pharmacology
Gene expression
Gene Expression Regulation
Health aspects
Immune response
Immune system
Immunoglobulins
Inflammation
Inflammation - genetics
Inflammation - immunology
Inflammation - metabolism
Inflammatory response
Innate immunity
Interleukin 6
Kinases
Life sciences
Macrophages
Macrophages - drug effects
Macrophages - immunology
Macrophages - metabolism
Macrophages, Peritoneal - drug effects
Macrophages, Peritoneal - immunology
Macrophages, Peritoneal - metabolism
Mammals
MAP Kinase Signaling System - drug effects
Mechanistic Target of Rapamycin Complex 1
Metabolism
Mice
Morpholines - pharmacology
Multiprotein Complexes - metabolism
NF-kappa B - metabolism
NF-κB protein
Pattern recognition
Penicillin
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphorylation
Proteins
Proto-Oncogene Proteins c-akt - metabolism
Rapamycin
Signal Transduction - drug effects
Stat3 protein
STAT3 Transcription Factor - metabolism
TLR5 protein
Toll-Like Receptor 5 - antagonists & inhibitors
Toll-Like Receptor 5 - metabolism
Toll-like receptors
TOR protein
TOR Serine-Threonine Kinases - metabolism
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
Viral infections
Wortmannin
title mTORC1 Regulates Flagellin-Induced Inflammatory Response in Macrophages
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