Identification of 34 novel proinflammatory proteins in a genome-wide macrophage functional screen
Signal transduction pathways activated by Toll-like Receptors and the IL-1 family of cytokines are fundamental to mounting an innate immune response and thus to clearing pathogens and promoting wound healing. Whilst mechanistic understanding of the regulation of innate signalling pathways has advanc...
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Veröffentlicht in: | PloS one 2012-07, Vol.7 (7), p.e42388-e42388 |
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creator | Wyllie, David H Søgaard, Karen C Holland, Karen Yaobo, Xu Bregu, Migena Hill, Adrian V S Kiss-Toth, Endre |
description | Signal transduction pathways activated by Toll-like Receptors and the IL-1 family of cytokines are fundamental to mounting an innate immune response and thus to clearing pathogens and promoting wound healing. Whilst mechanistic understanding of the regulation of innate signalling pathways has advanced considerably in recent years, there are still a number of critical controllers to be discovered. In order to characterise novel regulators of macrophage inflammation, we have carried out an extensive, cDNA-based forward genetic screen and identified 34 novel activators, based on their ability to induce the expression of cxcl2. Many are physiologically expressed in macrophages, although the majority of genes uncovered in our screen have not previously been linked to innate immunity. We show that expression of particular activators has profound but distinct impacts on LPS-induced inflammatory gene expression, including switch-type, amplifier and sensitiser behaviours. Furthermore, the novel genes identified here interact with the canonical inflammatory signalling network via specific mechanisms, as demonstrated by the use of dominant negative forms of IL1/TLR signalling mediators. |
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Whilst mechanistic understanding of the regulation of innate signalling pathways has advanced considerably in recent years, there are still a number of critical controllers to be discovered. In order to characterise novel regulators of macrophage inflammation, we have carried out an extensive, cDNA-based forward genetic screen and identified 34 novel activators, based on their ability to induce the expression of cxcl2. Many are physiologically expressed in macrophages, although the majority of genes uncovered in our screen have not previously been linked to innate immunity. We show that expression of particular activators has profound but distinct impacts on LPS-induced inflammatory gene expression, including switch-type, amplifier and sensitiser behaviours. Furthermore, the novel genes identified here interact with the canonical inflammatory signalling network via specific mechanisms, as demonstrated by the use of dominant negative forms of IL1/TLR signalling mediators.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0042388</identifier><identifier>PMID: 22860121</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Biology ; Cell Line ; Cellular signal transduction ; Clearing ; Cloning ; Cytokines ; Deoxyribonucleic acid ; DNA ; Gene expression ; Genes ; Genetic screening ; Genetic testing ; Genome ; Genomes ; Genomics ; Identification ; Immune response ; Immune system ; Immunity ; Inflammation ; Inflammation - metabolism ; Inflammation - physiopathology ; Innate immunity ; Interleukin 1 ; Kinases ; Library collections ; Lipopolysaccharides ; Macrophages ; Macrophages - physiology ; Medicine ; Mice ; Potassium ; Proteins ; Receptors ; Regulators ; Rodents ; Signal processing ; Signal Transduction ; Signaling ; Toll-like receptors ; Variance analysis ; Wound healing</subject><ispartof>PloS one, 2012-07, Vol.7 (7), p.e42388-e42388</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>Wyllie et al. 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Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2012 Wyllie et al 2012 Wyllie et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-237e15d7bafdd4871947aaa68313f73dc9af54b50b9896e1fe5060afb3781b173</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409161/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409161/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2096,2915,23845,27901,27902,53766,53768,79569,79570</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22860121$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Wyllie, David H</creatorcontrib><creatorcontrib>Søgaard, Karen C</creatorcontrib><creatorcontrib>Holland, Karen</creatorcontrib><creatorcontrib>Yaobo, Xu</creatorcontrib><creatorcontrib>Bregu, Migena</creatorcontrib><creatorcontrib>Hill, Adrian V S</creatorcontrib><creatorcontrib>Kiss-Toth, Endre</creatorcontrib><title>Identification of 34 novel proinflammatory proteins in a genome-wide macrophage functional screen</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Signal transduction pathways activated by Toll-like Receptors and the IL-1 family of cytokines are fundamental to mounting an innate immune response and thus to clearing pathogens and promoting wound healing. Whilst mechanistic understanding of the regulation of innate signalling pathways has advanced considerably in recent years, there are still a number of critical controllers to be discovered. In order to characterise novel regulators of macrophage inflammation, we have carried out an extensive, cDNA-based forward genetic screen and identified 34 novel activators, based on their ability to induce the expression of cxcl2. Many are physiologically expressed in macrophages, although the majority of genes uncovered in our screen have not previously been linked to innate immunity. We show that expression of particular activators has profound but distinct impacts on LPS-induced inflammatory gene expression, including switch-type, amplifier and sensitiser behaviours. 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Whilst mechanistic understanding of the regulation of innate signalling pathways has advanced considerably in recent years, there are still a number of critical controllers to be discovered. In order to characterise novel regulators of macrophage inflammation, we have carried out an extensive, cDNA-based forward genetic screen and identified 34 novel activators, based on their ability to induce the expression of cxcl2. Many are physiologically expressed in macrophages, although the majority of genes uncovered in our screen have not previously been linked to innate immunity. We show that expression of particular activators has profound but distinct impacts on LPS-induced inflammatory gene expression, including switch-type, amplifier and sensitiser behaviours. Furthermore, the novel genes identified here interact with the canonical inflammatory signalling network via specific mechanisms, as demonstrated by the use of dominant negative forms of IL1/TLR signalling mediators.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22860121</pmid><doi>10.1371/journal.pone.0042388</doi><tpages>e42388</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Biology Cell Line Cellular signal transduction Clearing Cloning Cytokines Deoxyribonucleic acid DNA Gene expression Genes Genetic screening Genetic testing Genome Genomes Genomics Identification Immune response Immune system Immunity Inflammation Inflammation - metabolism Inflammation - physiopathology Innate immunity Interleukin 1 Kinases Library collections Lipopolysaccharides Macrophages Macrophages - physiology Medicine Mice Potassium Proteins Receptors Regulators Rodents Signal processing Signal Transduction Signaling Toll-like receptors Variance analysis Wound healing |
title | Identification of 34 novel proinflammatory proteins in a genome-wide macrophage functional screen |
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