title: Transcriptional activation induced in macrophages by Toll-like receptor (TLR) ligands: from expression profiling to a model of TLR signaling.
abstract: Toll-like receptors (TLR) sense microbial compounds and bridge innate and adaptive immunity by activation of antigen-presenting cells. TLR-induced signaling via intracellular adaptor molecules, including MyD88 and TRIF, drives transcriptional activation of genes including pro-inflammatory cytokines and cell activation markers. To globally assess the activation programs triggered by individual TLR in macrophages, we used microarray-based gene expression profiling of the murine macrophage cell line RAW264.7. Here we describe that the TLR4 ligand LPS more strongly modulates gene expression compared to ligands for TLR 2, 3, 7, and 9. Taking advantage of the known dependency of TLR on given adaptor molecules, we operationally define sets of MyD88 and TRIF "private" genes. We conclude with a TLR signaling model that incorporates both negative and synergistic interactions of MyD88- and TRIF-controlled signaling pathways as deduced from the microarray data presented.
authors.affiliation: Institute of Medical Microbiology, Immunology and Hygiene, Technische Universität München, Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Schmitz
authors.forename: Jörg
authors.initials: J
authors.lastname: Mages
authors.forename: Antje
authors.initials: A
authors.lastname: Heit
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology / Q000378:metabolism; D015152:Blotting, Northern; D002460:Cell Line; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D008024:Ligands; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018448:Models, Immunological; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000943:Antigens, Differentiation; D016207:Cytokines; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse