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We investigated how TPL-2 controls transcription in TLR4-stimulated mouse macrophages. TPL-2 activation of ERK1\/2 regulated expression of genes encoding transcription factors, cytokines, chemokines, and signaling regulators. Bioinformatics analysis of gene clusters most rapidly induced by TPL-2 suggested that their transcription was mediated by the ternary complex factor (TCF) and FOS transcription factor families. Consistently, TPL-2 induced ERK1\/2 phosphorylation of the ELK1 TCF and the expression of TCF target genes. Furthermore, transcriptomic analysis of TCF-deficient macrophages demonstrated that TCFs mediate approximately half of the transcriptional output of TPL-2 signaling, partially via induced expression of secondary transcription factors. TPL-2 signaling and TCFs were required for maximal TLR4-induced FOS expression. Comparative analysis of the transcriptome of TLR4-stimulated Fos\u2212\/\u2212 macrophages indicated that TPL-2 regulated a significant fraction of genes by controlling FOS expression levels. A key function of this ERK1\/2-TCF-FOS pathway was to mediate TPL-2 suppression of type I IFN signaling, which is essential for host resistance against intracellular bacterial infection.<\/jats:p>","DOI":"10.4049\/jimmunol.2100213","type":"journal-article","created":{"date-parts":[[2022,1,26]],"date-time":"2022-01-26T22:35:11Z","timestamp":1643236511000},"page":"941-954","source":"Crossref","is-referenced-by-count":12,"title":["TPL-2 Inhibits IFN-\u03b2 Expression via an ERK1\/2-TCF-FOS Axis in TLR4-Stimulated Macrophages"],"prefix":"10.1093","volume":"208","author":[{"given":"Louise","family":"Blair","sequence":"first","affiliation":[{"name":"Immune Cell Signalling Laboratory, The Francis Crick Institute , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J","family":"Pattison","sequence":"additional","affiliation":[{"name":"Immune Cell Signalling Laboratory, The Francis Crick Institute , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1146-8824","authenticated-orcid":false,"given":"Probir","family":"Chakravarty","sequence":"additional","affiliation":[{"name":"Bioinformatics and Biostatistics Technology Platform, The Francis Crick Institute , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6665-8508","authenticated-orcid":false,"given":"Stamatia","family":"Papoutsopoulou","sequence":"additional","affiliation":[{"name":"Immune Cell Signalling Laboratory, The Francis Crick Institute , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6300-2420","authenticated-orcid":false,"given":"Latifa","family":"Bakiri","sequence":"additional","affiliation":[{"name":"Laboratory of Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna , Vienna,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin F","family":"Wagner","sequence":"additional","affiliation":[{"name":"Laboratory of Genes and Disease, Department of Laboratory Medicine, Medical University of Vienna , Vienna,","place":["Austria"]},{"name":"Laboratory of Genes and Disease, Department of Dermatology, Medical University of Vienna , Vienna,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Smale","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology and Molecular Genetics, University of California , Los Angeles, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5911-9223","authenticated-orcid":false,"given":"Steven C","family":"Ley","sequence":"additional","affiliation":[{"name":"Immune Cell Signalling Laboratory, The Francis Crick Institute , London,","place":["United Kingdom"]},{"name":"Department of Immunology and Inflammation, Imperial College London , London,","place":["United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"2025021008542245100_r1","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1038\/nri2634","article-title":"Transcriptional control of the inflammatory response","volume":"9","author":"Medzhitov","year":"2009","journal-title":"Nat. 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