{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T18:19:32Z","timestamp":1791137972158,"version":"4.1.0"},"reference-count":51,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2005,4,15]]},"abstract":"<jats:p>TLR4 (Toll-like receptor 4) is essential for sensing the endotoxin of Gram-negative bacteria. Mutations or deletion of the TLR4 gene in humans or mice have been associated with altered predisposition to or outcome of Gram-negative sepsis. In the present work, we studied the expression and regulation of the Tlr4 gene of mouse. In vivo, TLR4 levels were higher in macrophages compared with B, T or natural killer cells. High basal TLR4 promoter activity was observed in RAW 264.7, J774 and P388D1 macrophages transfected with a TLR4 promoter reporter vector. Analysis of truncated and mutated promoter constructs identified several positive [two Ets (E twenty-six) and one AP-1 (activator protein-1) sites] and negative (a GATA-like site and an octamer site) regulatory elements within 350\u00a0bp upstream of the transcriptional start site. The myeloid and B-cell-specific transcription factor PU.1 bound to the proximal Ets site. In contrast, none among PU.1, Ets-1, Ets-2 and Elk-1, but possibly one member of the ESE (epithelium-specific Ets) subfamily of Ets transcription factors, bound to the distal Ets site, which was indispensable for Tlr4 gene transcription. Endotoxin did not affect macrophage TLR4 promoter activity, but it decreased TLR4 steady-state mRNA levels by increasing the turnover of TLR4 transcripts. TLR4 expression was modestly altered by other pro- and anti-inflammatory stimuli, except for PMA plus ionomycin which strongly increased promoter activity and TLR4 mRNA levels. The mouse and human TLR4 genes were highly conserved. Yet, notable differences exist with respect to the elements implicated in gene regulation, which may account for species differences in terms of tissue expression and modulation by microbial and inflammatory stimuli.<\/jats:p>","DOI":"10.1042\/bj20041243","type":"journal-article","created":{"date-parts":[[2005,4,5]],"date-time":"2005-04-05T12:44:45Z","timestamp":1112705085000},"page":"355-365","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Critical role for Ets, AP-1 and GATA-like transcription factors in regulating mouse Toll-like receptor 4 (<i>Tlr4<\/i>) gene expression"],"prefix":"10.1042","volume":"387","author":[{"given":"Thierry","family":"ROGER","sequence":"first","affiliation":[{"name":"Infectious Diseases Service, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, BH19-111, rue du Bugnon 46, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"MICONNET","sequence":"additional","affiliation":[{"name":"Ludwig Institute for Cancer Research, University of Lausanne, Lausanne Branch, 1066 Epalinges, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Laure","family":"SCHIESSER","sequence":"additional","affiliation":[{"name":"Infectious Diseases Service, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, BH19-111, rue du Bugnon 46, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"KAI","sequence":"additional","affiliation":[{"name":"Division of Molecular Medicine, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, 862-0973 Kumamoto, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensuke","family":"MIYAKE","sequence":"additional","affiliation":[{"name":"Division of Infectious Genetics, Institute of Medical Science, University of Tokyo, 108-8639 Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thierry","family":"CALANDRA","sequence":"additional","affiliation":[{"name":"Infectious Diseases Service, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, BH19-111, rue du Bugnon 46, CH-1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2005,4,5]]},"reference":[{"key":"2021112217143562500_B1","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1126\/science.284.5418.1313","article-title":"Phylogenetic perspectives in innate immunity","volume":"284","author":"Hoffmann","year":"1999","journal-title":"Science"},{"key":"2021112217143562500_B2","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1146\/annurev.immunol.20.083001.084359","article-title":"Innate immune recognition","volume":"20","author":"Janeway","year":"2002","journal-title":"Annu. Rev. Immunol."},{"key":"2021112217143562500_B3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0952-7915(99)80004-1","article-title":"Recognition of Gram-negative bacteria and endotoxin by the innate immune system","volume":"11","author":"Ulevitch","year":"1999","journal-title":"Curr. Opin. Immunol."},{"key":"2021112217143562500_B4","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/ni0202-121","article-title":"Drosophila innate immunity: an evolutionary perspective","volume":"3","author":"Hoffmann","year":"2002","journal-title":"Nat. Immunol."},{"key":"2021112217143562500_B5","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1126\/science.282.5396.2085","article-title":"Defective LPS signaling in C3H\/HeJ and C57BL\/10ScCr mice: mutations in Tlr4 gene","volume":"282","author":"Poltorak","year":"1998","journal-title":"Science"},{"key":"2021112217143562500_B6","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1084\/jem.189.4.615","article-title":"Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4)","volume":"189","author":"Qureshi","year":"1999","journal-title":"J. Exp. Med."},{"key":"2021112217143562500_B7","doi-asserted-by":"crossref","first-page":"3749","DOI":"10.4049\/jimmunol.162.7.3749","article-title":"Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product","volume":"162","author":"Hoshino","year":"1999","journal-title":"J. Immunol."},{"key":"2021112217143562500_B8","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1038\/41131","article-title":"A human homologue of the Drosophila Toll protein signals activation of adaptive immunity","volume":"388","author":"Medzhitov","year":"1997","journal-title":"Nature (London)"},{"key":"2021112217143562500_B9","doi-asserted-by":"crossref","first-page":"20","DOI":"10.4049\/jimmunol.124.1.20","article-title":"Genetic control of susceptibility to Salmonella typhimurium in mice: role of the LPS gene","volume":"124","author":"O'Brien","year":"1980","journal-title":"J. Immunol."},{"key":"2021112217143562500_B10","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1084\/jem.189.11.1777","article-title":"MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4","volume":"189","author":"Shimazu","year":"1999","journal-title":"J. Exp. Med."},{"key":"2021112217143562500_B11","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/ni809","article-title":"Essential role of MD-2 in LPS responsiveness and TLR4 distribution","volume":"3","author":"Nagai","year":"2002","journal-title":"Nat. Immunol."},{"key":"2021112217143562500_B12","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1146\/annurev.immunol.21.120601.141126","article-title":"Toll-like receptors","volume":"21","author":"Takeda","year":"2003","journal-title":"Annu. Rev. Immunol."},{"key":"2021112217143562500_B13","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1126\/science.1094351","article-title":"A toll-like receptor that prevents infection by uropathogenic bacteria","volume":"303","author":"Zhang","year":"2004","journal-title":"Science"},{"key":"2021112217143562500_B14","doi-asserted-by":"crossref","first-page":"1529","DOI":"10.1126\/science.1093616","article-title":"Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA","volume":"303","author":"Diebold","year":"2004","journal-title":"Science"},{"key":"2021112217143562500_B15","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1126\/science.1093620","article-title":"Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8","volume":"303","author":"Heil","year":"2004","journal-title":"Science"},{"key":"2021112217143562500_B16","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1086\/344893","article-title":"Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections","volume":"186","author":"Agnese","year":"2002","journal-title":"J. Infect. Dis."},{"key":"2021112217143562500_B17","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1084\/jem.20031220","article-title":"A common dominant TLR5 stop codon polymorphism abolishes flagellin signaling and is associated with susceptibility to legionnaires' disease","volume":"198","author":"Hawn","year":"2003","journal-title":"J. Exp. Med."},{"key":"2021112217143562500_B18","doi-asserted-by":"crossref","first-page":"6075","DOI":"10.1073\/pnas.1031605100","article-title":"Assay of locus-specific genetic load implicates rare Toll-like receptor 4 mutations in meningococcal susceptibility","volume":"100","author":"Smirnova","year":"2003","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112217143562500_B19","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.4049\/jimmunol.164.7.3471","article-title":"Cutting edge: cell surface expression and lipopolysaccharide signaling via the toll-like receptor 4-MD-2 complex on mouse peritoneal macrophages","volume":"164","author":"Akashi","year":"2000","journal-title":"J. Immunol."},{"key":"2021112217143562500_B20","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1101\/gad.13.11.1398","article-title":"Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells","volume":"13","author":"Rekhtman","year":"1999","journal-title":"Genes Dev."},{"key":"2021112217143562500_B21","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/414920a","article-title":"MIF regulates innate immune responses through modulation of Toll-like receptor 4","volume":"414","author":"Roger","year":"2001","journal-title":"Nature (London)"},{"key":"2021112217143562500_B22","doi-asserted-by":"crossref","first-page":"7105","DOI":"10.1093\/emboj\/16.23.7105","article-title":"Using altered specificity Oct-1 and Oct-2 mutants to analyze the regulation of immunoglobulin gene transcription","volume":"16","author":"Shah","year":"1997","journal-title":"EMBO J."},{"key":"2021112217143562500_B23","doi-asserted-by":"crossref","first-page":"20098","DOI":"10.1074\/jbc.274.29.20098","article-title":"Myeloid ELF-1-like factor up-regulates lysozyme transcription in epithelial cells","volume":"274","author":"Kai","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B24","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1042\/bj3300429","article-title":"Enhanced AP-1 and NF-kappaB activities and stability of interleukin 8 (IL-8) transcripts are implicated in IL-8 mRNA superinduction in lung epithelial H292 cells","volume":"330","author":"Roger","year":"1998","journal-title":"Biochem. J."},{"key":"2021112217143562500_B25","doi-asserted-by":"crossref","first-page":"9773","DOI":"10.1074\/jbc.275.13.9773","article-title":"PU.1 and interferon consensus sequence-binding protein regulate the myeloid expression of the human Toll-like receptor 4 gene","volume":"275","author":"Rehli","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B26","doi-asserted-by":"crossref","first-page":"6975","DOI":"10.4049\/jimmunol.167.12.6975","article-title":"Bacterial peptidoglycan-induced tnf-alpha transcription is mediated through the transcription factors Egr-1, Elk-1, and NF-kappaB","volume":"167","author":"Xu","year":"2001","journal-title":"J. Immunol."},{"key":"2021112217143562500_B27","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1038\/35099076","article-title":"The ETS-domain transcription factor family","volume":"2","author":"Sharrocks","year":"2001","journal-title":"Nat. Rev. Mol. Cell. Biol."},{"key":"2021112217143562500_B28","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1182\/blood.V90.2.489","article-title":"Transcription factors, normal myeloid development, and leukemia","volume":"90","author":"Tenen","year":"1997","journal-title":"Blood"},{"key":"2021112217143562500_B29","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1126\/science.288.5470.1439","article-title":"Regulation of B lymphocyte and macrophage development by graded expression of PU.1","volume":"288","author":"DeKoter","year":"2000","journal-title":"Science"},{"key":"2021112217143562500_B30","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1128\/MCB.17.8.4419","article-title":"Isolation and characterization of a novel epithelium-specific transcription factor, ESE-1, a member of the ets family","volume":"17","author":"Oettgen","year":"1997","journal-title":"Mol. Cell. Biol."},{"key":"2021112217143562500_B31","doi-asserted-by":"crossref","first-page":"29439","DOI":"10.1074\/jbc.274.41.29439","article-title":"Characterization of ESE-2, a novel ESE-1-related Ets transcription factor that is restricted to glandular epithelium and differentiated keratinocytes","volume":"274","author":"Oettgen","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B32","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1074\/jbc.275.4.2986","article-title":"ESE-3, a novel member of an epithelium-specific ets transcription factor subfamily, demonstrates different target gene specificity from ESE-1","volume":"275","author":"Kas","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B33","doi-asserted-by":"crossref","first-page":"13957","DOI":"10.1074\/jbc.273.22.13957","article-title":"PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91(phox) expression","volume":"273","author":"Eklund","year":"1998","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B34","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.1182\/blood.V90.10.3984","article-title":"PU.1\/Pip and basic helix loop helix zipper transcription factors interact with binding sites in the CD20 promoter to help confer lineage- and stage-specific expression of CD20 in B lymphocytes","volume":"90","author":"Himmelmann","year":"1997","journal-title":"Blood"},{"key":"2021112217143562500_B35","doi-asserted-by":"crossref","first-page":"3285","DOI":"10.1074\/jbc.274.6.3285","article-title":"Developmental regulation of the kappa locus involves both positive and negative sequence elements in the 3\u2032 enhancer that affect synergy with the intron enhancer","volume":"274","author":"Liu","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B36","doi-asserted-by":"crossref","first-page":"6829","DOI":"10.4049\/jimmunol.166.11.6829","article-title":"PU.1 and multiple IFN regulatory factor proteins synergize to mediate transcriptional activation of the human IL-1 beta gene","volume":"166","author":"Marecki","year":"2001","journal-title":"J. Immunol."},{"key":"2021112217143562500_B37","doi-asserted-by":"crossref","first-page":"21909","DOI":"10.1074\/jbc.M212150200","article-title":"Multiple Ets factors and interferon regulatory factor-4 modulate CD68 expression in a cell type-specific manner","volume":"278","author":"O'Reilly","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2021112217143562500_B38","doi-asserted-by":"crossref","first-page":"2543","DOI":"10.1182\/blood.V95.8.2543","article-title":"GATA-1 interacts with the myeloid PU.1 transcription factor and represses PU.1-dependent transcription","volume":"95","author":"Nerlov","year":"2000","journal-title":"Blood"},{"key":"2021112217143562500_B39","doi-asserted-by":"crossref","first-page":"2608","DOI":"10.4049\/jimmunol.167.5.2608","article-title":"Regulation of IL-12 p40 promoter activity in primary human monocytes: roles of NF-kappaB, CCAAT\/enhancer-binding protein beta, and PU.1 and identification of a novel repressor element (GA-12) that responds to IL-4 and prostaglandin E(2)","volume":"167","author":"Becker","year":"2001","journal-title":"J. Immunol."},{"key":"2021112217143562500_B40","doi-asserted-by":"crossref","first-page":"2000","DOI":"10.4049\/jimmunol.163.4.2000","article-title":"Roles of IFN consensus sequence binding protein and PU.1 in regulating IL-18 gene expression","volume":"163","author":"Kim","year":"1999","journal-title":"J. Immunol."},{"key":"2021112217143562500_B41","doi-asserted-by":"crossref","first-page":"4135","DOI":"10.1182\/blood.V90.10.4135","article-title":"Murine macrophage mannose receptor promoter is regulated by the transcription factors PU.1 and SP1","volume":"90","author":"Eichbaum","year":"1997","journal-title":"Blood"},{"key":"2021112217143562500_B42","doi-asserted-by":"crossref","first-page":"6924","DOI":"10.4049\/jimmunol.167.12.6924","article-title":"NFkappaB and Sp1 elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium","volume":"167","author":"Wang","year":"2001","journal-title":"J. Immunol."},{"key":"2021112217143562500_B43","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1046\/j.1365-2141.1998.00863.x","article-title":"Molecular cloning and functional analysis of the CD33 promoter","volume":"102","author":"Bodger","year":"1998","journal-title":"Br. J. Haematol."},{"key":"2021112217143562500_B44","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1016\/S1471-4906(02)02259-7","article-title":"Of mice and men: species variations of Toll-like receptor expression","volume":"23","author":"Rehli","year":"2002","journal-title":"Trends Immunol."},{"key":"2021112217143562500_B45","doi-asserted-by":"crossref","first-page":"554","DOI":"10.4049\/jimmunol.168.2.554","article-title":"Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines","volume":"168","author":"Zarember","year":"2002","journal-title":"J. Immunol."},{"key":"2021112217143562500_B46","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1182\/blood.V99.9.3427","article-title":"Stimulation of toll-like receptor 4 expression in human mononuclear phagocytes by interferon-gamma: a molecular basis for priming and synergism with bacterial lipopolysaccharide","volume":"99","author":"Bosisio","year":"2002","journal-title":"Blood"},{"key":"2021112217143562500_B47","doi-asserted-by":"crossref","first-page":"249","DOI":"10.4049\/jimmunol.166.1.249","article-title":"Regulation of Toll-like receptors in human monocytes and dendritic cells","volume":"166","author":"Visintin","year":"2001","journal-title":"J. Immunol."},{"key":"2021112217143562500_B48","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1089\/10799900050163299","article-title":"Endotoxin and cytokine regulation of toll-like receptor (TLR) 2 and TLR4 gene expression in murine liver and hepatocytes","volume":"20","author":"Matsumura","year":"2000","journal-title":"J. Interferon Cytokine Res."},{"key":"2021112217143562500_B49","doi-asserted-by":"crossref","first-page":"3476","DOI":"10.4049\/jimmunol.164.7.3476","article-title":"Cutting edge: endotoxin tolerance in mouse peritoneal macrophages correlates with down-regulation of surface toll-like receptor 4 expression","volume":"164","author":"Nomura","year":"2000","journal-title":"J. Immunol."},{"key":"2021112217143562500_B50","doi-asserted-by":"crossref","first-page":"5252","DOI":"10.4049\/jimmunol.168.10.5252","article-title":"Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and lipopolysaccharide","volume":"168","author":"Fan","year":"2002","journal-title":"J. Immunol."},{"key":"2021112217143562500_B51","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1084\/jem.186.9.1535","article-title":"Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression","volume":"186","author":"Giese","year":"1997","journal-title":"J. Exp. Med."}],"container-title":["Biochemical Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/387\/2\/355\/720545\/bj3870355.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/portlandpress.com\/biochemj\/article-pdf\/387\/2\/355\/720545\/bj3870355.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,24]],"date-time":"2024-01-24T16:14:26Z","timestamp":1706112866000},"score":1,"resource":{"primary":{"URL":"https:\/\/portlandpress.com\/biochemj\/article\/387\/2\/355\/78783\/Critical-role-for-Ets-AP-1-and-GATA-like"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2005,4,5]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2005,4,15]]}},"URL":"https:\/\/doi.org\/10.1042\/bj20041243","relation":{},"ISSN":["0264-6021","1470-8728"],"issn-type":[{"value":"0264-6021","type":"print"},{"value":"1470-8728","type":"electronic"}],"subject":[],"published":{"date-parts":[[2005,4,5]]}}}