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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of experimental medicine 2012-02, Vol.209 (2), p.379-393
Hauptverfasser: Buxadé, Maria, Lunazzi, Giulia, Minguillón, Jordi, Iborra, Salvador, Berga-Bolaños, Rosa, Del Val, Margarita, Aramburu, José, López-Rodríguez, Cristina
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page 393
container_issue 2
container_start_page 379
container_title The Journal of experimental medicine
container_volume 209
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
format Article
fullrecord <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3280876</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>926893512</sourcerecordid><originalsourceid>FETCH-LOGICAL-c523t-d4c4b089585b886b2f59a42295ee00dfbddf46a1d136a49dced3055c1d7e858f3</originalsourceid><addsrcrecordid>eNqNUUtv1DAYtBCILoUbZ-QbF1L8-ZE4F6SqogWpgstythz7S9cliVM7qei_x0u3K7hxsCxrHp7REPIW2BkwLT_e4njGGQCoun1GNqAkq1ol9HOyYYzzChhrTsirnG8ZAylV_ZKccC6AA7ANwSuckOKvOWHOIU40TH516Gn3QLdxGKoh_ESa0OG8xJQLTEfrUpx39gZzAe7WUKR02SFdkp2yS2Fe9ka9dUVBv12eb9Vr8qK3Q8Y3h_uU_Lj8vL34Ul1_v_p6cX5dOcXFUnnpZMd0q7TqtK473qvWSs5bhciY7zvve1lb8CBqK1tfcgqmlAPfoFa6F6fk06PvvHYjFnwqmQYzpzDa9GCiDeZfZAo7cxPvjeCa6aYuBvBo4PLqzL52cnb5Izw-9oezhhsBSnFZNO8Pn6Z4t2JezBiyw2GwE8Y1m5bXuhUK-H8wQTXAm6YwPxxypJhzwv7YAZjZz27K7OZp9kJ_93fvI_lpZ_EbyLOqWw</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>921571277</pqid></control><display><type>article</type><title>Gene expression induced by Toll-like receptors in macrophages requires the transcription factor NFAT5</title><source>MEDLINE</source><source>Recercat</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><creator>Buxadé, Maria ; Lunazzi, Giulia ; Minguillón, Jordi ; Iborra, Salvador ; Berga-Bolaños, Rosa ; Del Val, Margarita ; Aramburu, José ; López-Rodríguez, Cristina</creator><creatorcontrib>Buxadé, Maria ; Lunazzi, Giulia ; Minguillón, Jordi ; Iborra, Salvador ; Berga-Bolaños, Rosa ; Del Val, Margarita ; Aramburu, José ; López-Rodríguez, Cristina</creatorcontrib><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><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 &lt;a href="http://creativecommons.org/licenses/by-nc-sa/3.0/"&gt;http://creativecommons.org/licenses/by-nc-sa/3.0/&lt;/a&gt;). &lt;a href="http://creativecommons.org/licenses/by-nc-sa/3.0/"&gt;http://creativecommons.org/licenses/by-nc-sa/3.0/&lt;/a&gt;</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>
fulltext fulltext
identifier ISSN: 0022-1007
ispartof The Journal of experimental medicine, 2012-02, Vol.209 (2), p.379-393
issn 0022-1007
1540-9538
language eng
recordid cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3280876
source MEDLINE; Recercat; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
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
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T03%3A34%3A09IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Gene%20expression%20induced%20by%20Toll-like%20receptors%20in%20macrophages%20requires%20the%20transcription%20factor%20NFAT5&rft.jtitle=The%20Journal%20of%20experimental%20medicine&rft.au=Buxad%C3%A9,%20Maria&rft.date=2012-02-13&rft.volume=209&rft.issue=2&rft.spage=379&rft.epage=393&rft.pages=379-393&rft.issn=0022-1007&rft.eissn=1540-9538&rft_id=info:doi/10.1084/jem.20111569&rft_dat=%3Cproquest_pubme%3E926893512%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=921571277&rft_id=info:pmid/22312110&rfr_iscdi=true