Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5
Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osm...
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Veröffentlicht in: | The Journal of experimental medicine 2012-02, Vol.209 (2), p.379-393 |
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creator | Buxadé, Maria Lunazzi, Giulia Minguillón, Jordi Iborra, Salvador Berga-Bolaños, Rosa Del Val, Margarita Aramburu, José López-Rodríguez, Cristina |
description | Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses. |
doi_str_mv | 10.1084/jem.20111569 |
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We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.</description><identifier>ISSN: 0022-1007</identifier><identifier>EISSN: 1540-9538</identifier><identifier>DOI: 10.1084/jem.20111569</identifier><identifier>PMID: 22312110</identifier><language>eng</language><publisher>United States: Rockefeller University Press</publisher><subject>Animals ; Chromatin Immunoprecipitation ; Cèl·lules T ; DNA Primers - genetics ; Factors de transcripció ; Flow Cytometry ; Gene Expression Regulation - genetics ; Gene Expression Regulation - immunology ; Gene Regulatory Networks - genetics ; Gene Regulatory Networks - immunology ; I-kappa B Kinase - metabolism ; Immunoblotting ; Interleukin-6 - metabolism ; Leishmania - immunology ; Leishmania major ; Luciferases ; Macrophages - metabolism ; Metabolisme ; Mice ; Mice, Knockout ; Microarray Analysis ; Nitric Oxide Synthase Type II - metabolism ; Nitrites - metabolism ; Plasmids - genetics ; Receptors ; Regulació genètica ; Toll-Like Receptors - metabolism ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>The Journal of experimental medicine, 2012-02, Vol.209 (2), p.379-393</ispartof><rights>info:eu-repo/semantics/openAccess This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">http://creativecommons.org/licenses/by-nc-sa/3.0/</a>). <a href="http://creativecommons.org/licenses/by-nc-sa/3.0/">http://creativecommons.org/licenses/by-nc-sa/3.0/</a></rights><rights>2012 Buxadé et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c523t-d4c4b089585b886b2f59a42295ee00dfbddf46a1d136a49dced3055c1d7e858f3</citedby><cites>FETCH-LOGICAL-c523t-d4c4b089585b886b2f59a42295ee00dfbddf46a1d136a49dced3055c1d7e858f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,26953,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22312110$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Buxadé, Maria</creatorcontrib><creatorcontrib>Lunazzi, Giulia</creatorcontrib><creatorcontrib>Minguillón, Jordi</creatorcontrib><creatorcontrib>Iborra, Salvador</creatorcontrib><creatorcontrib>Berga-Bolaños, Rosa</creatorcontrib><creatorcontrib>Del Val, Margarita</creatorcontrib><creatorcontrib>Aramburu, José</creatorcontrib><creatorcontrib>López-Rodríguez, Cristina</creatorcontrib><title>Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5</title><title>The Journal of experimental medicine</title><addtitle>J Exp Med</addtitle><description>Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.</description><subject>Animals</subject><subject>Chromatin Immunoprecipitation</subject><subject>Cèl·lules T</subject><subject>DNA Primers - genetics</subject><subject>Factors de transcripció</subject><subject>Flow Cytometry</subject><subject>Gene Expression Regulation - genetics</subject><subject>Gene Expression Regulation - immunology</subject><subject>Gene Regulatory Networks - genetics</subject><subject>Gene Regulatory Networks - immunology</subject><subject>I-kappa B Kinase - metabolism</subject><subject>Immunoblotting</subject><subject>Interleukin-6 - metabolism</subject><subject>Leishmania - immunology</subject><subject>Leishmania major</subject><subject>Luciferases</subject><subject>Macrophages - metabolism</subject><subject>Metabolisme</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microarray Analysis</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitrites - metabolism</subject><subject>Plasmids - genetics</subject><subject>Receptors</subject><subject>Regulació genètica</subject><subject>Toll-Like Receptors - metabolism</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>0022-1007</issn><issn>1540-9538</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>XX2</sourceid><recordid>eNqNUUtv1DAYtBCILoUbZ-QbF1L8-ZE4F6SqogWpgstythz7S9cliVM7qei_x0u3K7hxsCxrHp7REPIW2BkwLT_e4njGGQCoun1GNqAkq1ol9HOyYYzzChhrTsirnG8ZAylV_ZKccC6AA7ANwSuckOKvOWHOIU40TH516Gn3QLdxGKoh_ESa0OG8xJQLTEfrUpx39gZzAe7WUKR02SFdkp2yS2Fe9ka9dUVBv12eb9Vr8qK3Q8Y3h_uU_Lj8vL34Ul1_v_p6cX5dOcXFUnnpZMd0q7TqtK473qvWSs5bhciY7zvve1lb8CBqK1tfcgqmlAPfoFa6F6fk06PvvHYjFnwqmQYzpzDa9GCiDeZfZAo7cxPvjeCa6aYuBvBo4PLqzL52cnb5Izw-9oezhhsBSnFZNO8Pn6Z4t2JezBiyw2GwE8Y1m5bXuhUK-H8wQTXAm6YwPxxypJhzwv7YAZjZz27K7OZp9kJ_93fvI_lpZ_EbyLOqWw</recordid><startdate>20120213</startdate><enddate>20120213</enddate><creator>Buxadé, Maria</creator><creator>Lunazzi, Giulia</creator><creator>Minguillón, Jordi</creator><creator>Iborra, Salvador</creator><creator>Berga-Bolaños, Rosa</creator><creator>Del Val, Margarita</creator><creator>Aramburu, José</creator><creator>López-Rodríguez, Cristina</creator><general>Rockefeller University Press</general><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>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>XX2</scope><scope>5PM</scope></search><sort><creationdate>20120213</creationdate><title>Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5</title><author>Buxadé, Maria ; Lunazzi, Giulia ; Minguillón, Jordi ; Iborra, Salvador ; Berga-Bolaños, Rosa ; Del Val, Margarita ; Aramburu, José ; López-Rodríguez, Cristina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c523t-d4c4b089585b886b2f59a42295ee00dfbddf46a1d136a49dced3055c1d7e858f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Chromatin Immunoprecipitation</topic><topic>Cèl·lules T</topic><topic>DNA Primers - genetics</topic><topic>Factors de transcripció</topic><topic>Flow Cytometry</topic><topic>Gene Expression Regulation - genetics</topic><topic>Gene Expression Regulation - immunology</topic><topic>Gene Regulatory Networks - genetics</topic><topic>Gene Regulatory Networks - immunology</topic><topic>I-kappa B Kinase - metabolism</topic><topic>Immunoblotting</topic><topic>Interleukin-6 - metabolism</topic><topic>Leishmania - immunology</topic><topic>Leishmania major</topic><topic>Luciferases</topic><topic>Macrophages - metabolism</topic><topic>Metabolisme</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Microarray Analysis</topic><topic>Nitric Oxide Synthase Type II - metabolism</topic><topic>Nitrites - metabolism</topic><topic>Plasmids - genetics</topic><topic>Receptors</topic><topic>Regulació genètica</topic><topic>Toll-Like Receptors - metabolism</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Buxadé, Maria</creatorcontrib><creatorcontrib>Lunazzi, Giulia</creatorcontrib><creatorcontrib>Minguillón, Jordi</creatorcontrib><creatorcontrib>Iborra, Salvador</creatorcontrib><creatorcontrib>Berga-Bolaños, Rosa</creatorcontrib><creatorcontrib>Del Val, Margarita</creatorcontrib><creatorcontrib>Aramburu, José</creatorcontrib><creatorcontrib>López-Rodríguez, Cristina</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>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Recercat</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>Buxadé, Maria</au><au>Lunazzi, Giulia</au><au>Minguillón, Jordi</au><au>Iborra, Salvador</au><au>Berga-Bolaños, Rosa</au><au>Del Val, Margarita</au><au>Aramburu, José</au><au>López-Rodríguez, Cristina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5</atitle><jtitle>The Journal of experimental medicine</jtitle><addtitle>J Exp Med</addtitle><date>2012-02-13</date><risdate>2012</risdate><volume>209</volume><issue>2</issue><spage>379</spage><epage>393</epage><pages>379-393</pages><issn>0022-1007</issn><eissn>1540-9538</eissn><abstract>Toll-like receptors (TLRs) engage networks of transcriptional regulators to induce genes essential for antimicrobial immunity. We report that NFAT5, previously characterized as an osmostress responsive factor, regulates the expression of multiple TLR-induced genes in macrophages independently of osmotic stress. NFAT5 was essential for the induction of the key antimicrobial gene Nos2 (inducible nitric oxide synthase [iNOS]) in response to low and high doses of TLR agonists but is required for Tnf and Il6 mainly under mild stimulatory conditions, indicating that NFAT5 could regulate specific gene patterns depending on pathogen burden intensity. NFAT5 exhibited two modes of association with target genes, as it was constitutively bound to Tnf and other genes regardless of TLR stimulation, whereas its recruitment to Nos2 or Il6 required TLR activation. Further analysis revealed that TLR-induced recruitment of NFAT5 to Nos2 was dependent on inhibitor of κB kinase (IKK) β activity and de novo protein synthesis, and was sensitive to histone deacetylases. In vivo, NFAT5 was necessary for effective immunity against Leishmania major, a parasite whose clearance requires TLRs and iNOS expression in macrophages. These findings identify NFAT5 as a novel regulator of mammalian anti-pathogen responses.</abstract><cop>United States</cop><pub>Rockefeller University Press</pub><pmid>22312110</pmid><doi>10.1084/jem.20111569</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Chromatin Immunoprecipitation Cèl·lules T DNA Primers - genetics Factors de transcripció Flow Cytometry Gene Expression Regulation - genetics Gene Expression Regulation - immunology Gene Regulatory Networks - genetics Gene Regulatory Networks - immunology I-kappa B Kinase - metabolism Immunoblotting Interleukin-6 - metabolism Leishmania - immunology Leishmania major Luciferases Macrophages - metabolism Metabolisme Mice Mice, Knockout Microarray Analysis Nitric Oxide Synthase Type II - metabolism Nitrites - metabolism Plasmids - genetics Receptors Regulació genètica Toll-Like Receptors - metabolism Transcription Factors - genetics Transcription Factors - metabolism Tumor Necrosis Factor-alpha - metabolism |
title | Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5 |
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