Negative Regulation of Toll-like-Receptor Signaling by IRF-4
The recognition of microbial components by Toll-like receptors (TLRs) is an event central to the activation of innate and adaptive immune systems. TLR activation triggers the induction of down-stream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecule...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-11, Vol.102 (44), p.15989-15994 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Negishi, Hideo Ohba, Yusuke Yanai, Hideyuki Takaoka, Akinori Honma, Kiri Yui, Katsuyuki Matsuyama, Toshifumi Taniguchi, Tadatsugu Honda, Kenya |
| description | The recognition of microbial components by Toll-like receptors (TLRs) is an event central to the activation of innate and adaptive immune systems. TLR activation triggers the induction of down-stream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs. |
| doi_str_mv | 10.1073/pnas.0508327102 |
| format | Article |
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TLR activation triggers the induction of down-stream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0508327102</identifier><identifier>PMID: 16236719</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Antigens, Differentiation - metabolism ; Biological Sciences ; Bone marrow cells ; Cytokines ; Cytokines - blood ; Delta cells ; Gene Expression Regulation ; Genes ; HEK293 cells ; Hypersensitivity ; Immune system ; Immunology ; Inductive reasoning ; Interferon Regulatory Factor-7 - metabolism ; Interferon Regulatory Factors - genetics ; Interferon Regulatory Factors - immunology ; Interferon Regulatory Factors - metabolism ; Interferon Regulatory Factors - physiology ; Macrophages ; Macrophages, Peritoneal - immunology ; Messenger RNA ; Mice ; Mice, Knockout ; Molecules ; Myeloid Differentiation Factor 88 ; Peritoneal macrophages ; Receptors, Immunologic - metabolism ; Rodents ; Signal Transduction ; Toll-Like Receptors - immunology ; Toll-Like Receptors - metabolism</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2005-11, Vol.102 (44), p.15989-15994</ispartof><rights>Copyright 2005 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Nov 1, 2005</rights><rights>Copyright © 2005, The National Academy of Sciences 2005</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c641t-41f2d028bd3284fc364a7d9cecd086cbc8fc56b9d347ee6d636bbd448b013bb73</citedby><cites>FETCH-LOGICAL-c641t-41f2d028bd3284fc364a7d9cecd086cbc8fc56b9d347ee6d636bbd448b013bb73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/102/44.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/4143312$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/4143312$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27923,27924,53790,53792,58016,58249</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16236719$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Negishi, Hideo</creatorcontrib><creatorcontrib>Ohba, Yusuke</creatorcontrib><creatorcontrib>Yanai, Hideyuki</creatorcontrib><creatorcontrib>Takaoka, Akinori</creatorcontrib><creatorcontrib>Honma, Kiri</creatorcontrib><creatorcontrib>Yui, Katsuyuki</creatorcontrib><creatorcontrib>Matsuyama, Toshifumi</creatorcontrib><creatorcontrib>Taniguchi, Tadatsugu</creatorcontrib><creatorcontrib>Honda, Kenya</creatorcontrib><title>Negative Regulation of Toll-like-Receptor Signaling by IRF-4</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The recognition of microbial components by Toll-like receptors (TLRs) is an event central to the activation of innate and adaptive immune systems. TLR activation triggers the induction of down-stream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs.</description><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Antigens, Differentiation - metabolism</subject><subject>Biological Sciences</subject><subject>Bone marrow cells</subject><subject>Cytokines</subject><subject>Cytokines - blood</subject><subject>Delta cells</subject><subject>Gene Expression Regulation</subject><subject>Genes</subject><subject>HEK293 cells</subject><subject>Hypersensitivity</subject><subject>Immune system</subject><subject>Immunology</subject><subject>Inductive reasoning</subject><subject>Interferon Regulatory Factor-7 - metabolism</subject><subject>Interferon Regulatory Factors - genetics</subject><subject>Interferon Regulatory Factors - immunology</subject><subject>Interferon Regulatory Factors - metabolism</subject><subject>Interferon Regulatory Factors - physiology</subject><subject>Macrophages</subject><subject>Macrophages, Peritoneal - immunology</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Molecules</subject><subject>Myeloid Differentiation Factor 88</subject><subject>Peritoneal macrophages</subject><subject>Receptors, Immunologic - metabolism</subject><subject>Rodents</subject><subject>Signal Transduction</subject><subject>Toll-Like Receptors - immunology</subject><subject>Toll-Like Receptors - metabolism</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0c9rFDEUB_Agil2rZy8ig4eCh2lfficgghSrhaKw1nNIMplx1uxkO5kp7X9vll266qWnBPJ5Ly_5IvQawykGSc82g82nwEFRIjGQJ2iBQeNaMA1P0QKAyFoxwo7Qi5xXAKC5gufoCAtChcR6gT58C52d-ttQLUM3x7JNQ5Xa6jrFWMf-d6iXwYfNlMbqR98NNvZDV7n76nJ5UbOX6FlrYw6v9usx-nnx-fr8a331_cvl-aer2guGp5rhljRAlGsoUaz1VDArG-2Db0AJ77xqPRdON5TJEEQjqHCuYUw5wNQ5SY_Rx13fzezWofFhmEYbzWbs13a8N8n25t-Tof9lunRrMOFSMl0anOwbjOlmDnky6z77EKMdQpqzEUpyDYQ9CrGkWgnOC3z3H1yleSz_kw0pU2tO1Pbasx3yY8p5DO3DyBjMNj-zzc8c8isVb_9-6cHvAyvg_R5sKw_tiGHMYK6VNu0c4xTupmKrR2whb3ZklUvED4ZhRikm9A-UOrfb</recordid><startdate>20051101</startdate><enddate>20051101</enddate><creator>Negishi, Hideo</creator><creator>Ohba, Yusuke</creator><creator>Yanai, Hideyuki</creator><creator>Takaoka, Akinori</creator><creator>Honma, Kiri</creator><creator>Yui, Katsuyuki</creator><creator>Matsuyama, Toshifumi</creator><creator>Taniguchi, Tadatsugu</creator><creator>Honda, Kenya</creator><general>National Academy of Sciences</general><general>National Acad Sciences</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20051101</creationdate><title>Negative Regulation of Toll-like-Receptor Signaling by IRF-4</title><author>Negishi, Hideo ; 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TLR activation triggers the induction of down-stream target genes, wherein the TLR-interacting adaptor molecule MyD88 recruits various signaling molecules and transcription factors. Two members of the IFN regulatory factor (IRF) family of transcription factors, IRF-5 and IRF-7, interact with MyD88 and induce proinflammatory cytokines and type I IFNs, respectively. Here, we show that IRF-4 also interacts with MyD88 and acts as a negative regulator of TLR signaling. IRF-4 mRNA is induced by TLR activation, and IRF-4 competes with IRF-5, but not with IRF-7, for MyD88 interaction. The TLR-dependent induction of proinflammatory cytokines is markedly enhanced in peritoneal macrophages from mice deficient in the Irf4 gene, whereas the induction is inhibited by the ectopic expression of IRF-4 in a macrophage cell line. The critical function of IRF-4 in TLR signaling in vivo is underscored by the observation that Irf4-deficient mice show hypersensitivity to DNA-induced shock, with elevated serum proinflammatory cytokine levels. This study may provide an insight into the complex regulatory mechanisms of MyD88 signaling by IRFs.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>16236719</pmid><doi>10.1073/pnas.0508327102</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - metabolism Animals Antigens, Differentiation - metabolism Biological Sciences Bone marrow cells Cytokines Cytokines - blood Delta cells Gene Expression Regulation Genes HEK293 cells Hypersensitivity Immune system Immunology Inductive reasoning Interferon Regulatory Factor-7 - metabolism Interferon Regulatory Factors - genetics Interferon Regulatory Factors - immunology Interferon Regulatory Factors - metabolism Interferon Regulatory Factors - physiology Macrophages Macrophages, Peritoneal - immunology Messenger RNA Mice Mice, Knockout Molecules Myeloid Differentiation Factor 88 Peritoneal macrophages Receptors, Immunologic - metabolism Rodents Signal Transduction Toll-Like Receptors - immunology Toll-Like Receptors - metabolism |
| title | Negative Regulation of Toll-like-Receptor Signaling by IRF-4 |
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