title: Species-specific regulation of Toll-like receptor 3 genes in men and mice.
abstract: Toll-like receptor 3 (TLR3) belongs to a family of evolutionary conserved innate immune recognition molecules and recognizes double-stranded RNA, a molecular pattern associated with viral infections. Earlier studies suggested a differential expression pattern in men and mice; the molecular basis for this observation, however, was unknown. Here we demonstrate that species-specific differences in tissue expression and responses to lipopolysaccaride (LPS) coincide with the presence of different, evolutionary non-conserved promoter sequences in both species. Despite the overall unrelatedness of TLR3 promoter sequences, mRNA expression of both TLR3 orthologues was induced by interferons, particularly by interferon (IFN)-beta. The basal and IFN-beta-induced activation of promoters from both species largely depended on similar interferon regulatory factor (IRF) elements, which constitutively bound IRF-2 and recruited IRF-1 after stimulation. In murine macrophages, IFN-beta-induced TLR3 up-regulation required IFNAR1, STAT1, and in part IRF-1, but not the Janus kinase (Jak) family member Tyk2. We also show that LPS specifically up-regulates TLR3 expression in murine cells through the induction of autocrine/paracrine IFN-beta. In humans, however, IFN-beta-induced up-regulation of TLR3 was blocked by pretreatment with LPS, despite the efficient induction of IRF-1. Our findings reveal a mechanistic basis for the observed differences as well as similarities in TLR3 expression in men and mice. The IFN-beta-TLR3 link further suggests a role of TLR3 in innate and adaptive immune responses to viral infections. It will be interesting and important to clarify whether the observed differences in the transcriptional regulation of TLR3 influence innate immune responses in a species-specific manner.
authors.affiliation: Department of Hematology and Oncology, University of Regensburg, 93042 Regensburg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Heinz
authors.forename: Viola
authors.initials: V
authors.lastname: Haehnel
authors.forename: Marina
authors.initials: M
authors.lastname: Karaghiosoff
authors.forename: Lucia
authors.initials: L
authors.lastname: Schwarzfischer
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Krause
authors.forename: Michael
authors.initials: M
authors.lastname: Rehli
mesh_terms: D000818:Animals; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019143:Evolution, Molecular; D005091:Exons; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D016899:Interferon-beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000378:metabolism; D012330:RNA, Double-Stranded; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics*; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013045:Species Specificity; D053634:TYK2 Kinase; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494229:IRF2 protein, human; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D011506:Proteins; D012330:RNA, Double-Stranded; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D014157:Transcription Factors; D016899:Interferon-beta; D004247:DNA; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C070139:TYK2 protein, human; C499356:Tyk2 protein, mouse