Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses
Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated...
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| Veröffentlicht in: | The Journal of experimental medicine 2009-08, Vol.206 (9), p.2027-2035 |
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| container_title | The Journal of experimental medicine |
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| creator | Kimura, Akihiro Naka, Tetsuji Nakahama, Taisuke Chinen, Ichino Masuda, Kazuya Nohara, Keiko Fujii-Kuriyama, Yoshiaki Kishimoto, Tadamitsu |
| description | Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-beta plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-alpha by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-kappaB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1. |
| doi_str_mv | 10.1084/jem.20090560 |
| format | Article |
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In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-beta plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-alpha by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-kappaB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20090560</identifier><identifier>PMID: 19703987</identifier><language>eng</language><publisher>United States: The Rockefeller University Press</publisher><subject>Animals ; Blotting, Western ; Chromatin Immunoprecipitation ; DNA Primers - genetics ; Enzyme-Linked Immunosorbent Assay ; Gene Expression Regulation - immunology ; Immunoprecipitation ; Inflammation - immunology ; Inflammation - metabolism ; Interleukin-6 - immunology ; Interleukin-6 - metabolism ; Lipopolysaccharides ; Luciferases ; Macrophages - immunology ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes - immunology ; Multiprotein Complexes - metabolism ; NF-kappa B - metabolism ; Receptors, Aryl Hydrocarbon - immunology ; Receptors, Aryl Hydrocarbon - metabolism ; Signal Transduction - immunology ; STAT1 Transcription Factor - immunology ; STAT1 Transcription Factor - metabolism ; Tumor Necrosis Factor-alpha - immunology</subject><ispartof>The Journal of experimental medicine, 2009-08, Vol.206 (9), p.2027-2035</ispartof><rights>2009 Kimura et al. 2009</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c382t-88464d204abef03a1154ca7e9d3b96847616df20296b3801d7fd4580cbbc94c73</citedby><cites>FETCH-LOGICAL-c382t-88464d204abef03a1154ca7e9d3b96847616df20296b3801d7fd4580cbbc94c73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19703987$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kimura, Akihiro</creatorcontrib><creatorcontrib>Naka, Tetsuji</creatorcontrib><creatorcontrib>Nakahama, Taisuke</creatorcontrib><creatorcontrib>Chinen, Ichino</creatorcontrib><creatorcontrib>Masuda, Kazuya</creatorcontrib><creatorcontrib>Nohara, Keiko</creatorcontrib><creatorcontrib>Fujii-Kuriyama, Yoshiaki</creatorcontrib><creatorcontrib>Kishimoto, Tadamitsu</creatorcontrib><title>Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-beta plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-alpha by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-kappaB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1.</description><subject>Animals</subject><subject>Blotting, Western</subject><subject>Chromatin Immunoprecipitation</subject><subject>DNA Primers - genetics</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Gene Expression Regulation - immunology</subject><subject>Immunoprecipitation</subject><subject>Inflammation - immunology</subject><subject>Inflammation - metabolism</subject><subject>Interleukin-6 - immunology</subject><subject>Interleukin-6 - metabolism</subject><subject>Lipopolysaccharides</subject><subject>Luciferases</subject><subject>Macrophages - immunology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Multiprotein Complexes - immunology</subject><subject>Multiprotein Complexes - metabolism</subject><subject>NF-kappa B - metabolism</subject><subject>Receptors, Aryl Hydrocarbon - immunology</subject><subject>Receptors, Aryl Hydrocarbon - metabolism</subject><subject>Signal Transduction - immunology</subject><subject>STAT1 Transcription Factor - immunology</subject><subject>STAT1 Transcription Factor - metabolism</subject><subject>Tumor Necrosis Factor-alpha - immunology</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkU1P3DAQhq2qqGyht56rnHpqYPwRf1yQEKIt0kpUopxdx3ZYoyRebAe0_x5XbGl7sjR-5p0ZPQh9xHCCQbLTez-dEAAFHYc3aIU7Bq3qqHyLVgCEtBhAHKL3Od8DYMY6_g4dYiWAKilW6Nd52o3NZudStCb1cW6St35bYmrC3Ng49WE2JdT6Uyib5qaYgityt4ym-Nysf9y0YXaL9a7yw2imydTeXUXyNs7Z52N0MJgx-w_79wjdfr38efG9XV9_u7o4X7eWSlJaKRlnjgAzvR-AGlzvsEZ45WivuGSCY-4GAkTxnkrATgyOdRJs31vFrKBH6Owld7v0k3fWzyWZUW9TmEza6WiC_v9nDht9Fx81EVRgTmvA531Aig-Lz0VPIVs_jmb2ccmaC04UBlbBLy-gTTHn5IfXIRj0byW6KtF_lFT807-L_YX3DugzgdmJyA</recordid><startdate>20090831</startdate><enddate>20090831</enddate><creator>Kimura, Akihiro</creator><creator>Naka, Tetsuji</creator><creator>Nakahama, Taisuke</creator><creator>Chinen, Ichino</creator><creator>Masuda, Kazuya</creator><creator>Nohara, Keiko</creator><creator>Fujii-Kuriyama, Yoshiaki</creator><creator>Kishimoto, Tadamitsu</creator><general>The Rockefeller University Press</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090831</creationdate><title>Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses</title><author>Kimura, Akihiro ; Naka, Tetsuji ; Nakahama, Taisuke ; Chinen, Ichino ; Masuda, Kazuya ; Nohara, Keiko ; Fujii-Kuriyama, Yoshiaki ; Kishimoto, Tadamitsu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c382t-88464d204abef03a1154ca7e9d3b96847616df20296b3801d7fd4580cbbc94c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Blotting, Western</topic><topic>Chromatin Immunoprecipitation</topic><topic>DNA Primers - genetics</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Gene Expression Regulation - immunology</topic><topic>Immunoprecipitation</topic><topic>Inflammation - immunology</topic><topic>Inflammation - metabolism</topic><topic>Interleukin-6 - immunology</topic><topic>Interleukin-6 - metabolism</topic><topic>Lipopolysaccharides</topic><topic>Luciferases</topic><topic>Macrophages - immunology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Multiprotein Complexes - immunology</topic><topic>Multiprotein Complexes - metabolism</topic><topic>NF-kappa B - metabolism</topic><topic>Receptors, Aryl Hydrocarbon - immunology</topic><topic>Receptors, Aryl Hydrocarbon - metabolism</topic><topic>Signal Transduction - immunology</topic><topic>STAT1 Transcription Factor - immunology</topic><topic>STAT1 Transcription Factor - metabolism</topic><topic>Tumor Necrosis Factor-alpha - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kimura, Akihiro</creatorcontrib><creatorcontrib>Naka, Tetsuji</creatorcontrib><creatorcontrib>Nakahama, Taisuke</creatorcontrib><creatorcontrib>Chinen, Ichino</creatorcontrib><creatorcontrib>Masuda, Kazuya</creatorcontrib><creatorcontrib>Nohara, Keiko</creatorcontrib><creatorcontrib>Fujii-Kuriyama, Yoshiaki</creatorcontrib><creatorcontrib>Kishimoto, Tadamitsu</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of experimental medicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kimura, Akihiro</au><au>Naka, Tetsuji</au><au>Nakahama, Taisuke</au><au>Chinen, Ichino</au><au>Masuda, Kazuya</au><au>Nohara, Keiko</au><au>Fujii-Kuriyama, Yoshiaki</au><au>Kishimoto, Tadamitsu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2009-08-31</date><risdate>2009</risdate><volume>206</volume><issue>9</issue><spage>2027</spage><epage>2035</epage><pages>2027-2035</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Toll-like receptor (TLR) signals perform a crucial role in innate immune responses to pathogens. In this study, we found that the aryl hydrocarbon receptor (Ahr) negatively regulates inflammatory responses mediated by lipopolysaccharide (LPS) in macrophages. Ahr was induced in macrophages stimulated by LPS, but not by transforming growth factor (TGF)-beta plus interleukin (IL)-6, which can induce Ahr in naive T cells. The production of IL-6 and tumor necrosis factor (TNF)-alpha by LPS was significantly elevated in Ahr-deficient macrophages compared with that in wild-type (WT) cells. Ahr-deficient mice were more highly sensitive to LPS-induced lethal shock than WT mice. Signal transducer and activator of transcription 1 (Stat1) deficiency, as well as Ahr deficiency, augmented LPS-induced IL-6 production. We found that Ahr forms a complex with Stat1 and nuclear factor-kappa B (NF-kappaB) in macrophages stimulated by LPS, which leads to inhibition of the promoter activity of IL-6. Ahr thus plays an essential role in the negative regulation of the LPS signaling pathway through interaction with Stat1.</abstract><cop>United States</cop><pub>The Rockefeller University Press</pub><pmid>19703987</pmid><doi>10.1084/jem.20090560</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Blotting, Western Chromatin Immunoprecipitation DNA Primers - genetics Enzyme-Linked Immunosorbent Assay Gene Expression Regulation - immunology Immunoprecipitation Inflammation - immunology Inflammation - metabolism Interleukin-6 - immunology Interleukin-6 - metabolism Lipopolysaccharides Luciferases Macrophages - immunology Mice Mice, Inbred C57BL Multiprotein Complexes - immunology Multiprotein Complexes - metabolism NF-kappa B - metabolism Receptors, Aryl Hydrocarbon - immunology Receptors, Aryl Hydrocarbon - metabolism Signal Transduction - immunology STAT1 Transcription Factor - immunology STAT1 Transcription Factor - metabolism Tumor Necrosis Factor-alpha - immunology |
| title | Aryl hydrocarbon receptor in combination with Stat1 regulates LPS-induced inflammatory responses |
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