title: Toll-like receptor 1 inhibits Toll-like receptor 4 signaling in endothelial cells.
abstract: Toll-like receptor 4 (TLR4) is the signal-transducing component of the LPS recognition complex and is essential for LPS-induced septic shock. Here we demonstrate that TLR1 has the capacity to abrogate TLR4 signaling. Human microvascular endothelial cells express TLR4 but not TLR1 and respond to LPS through TLR4. The ability of these cells to respond to LPS was lost, however, when they were transfected with TLR1. Inhibition was specific for TLR1 because TL5 failed to block TLR4 function. Moreover, TLR1 had no effect upon TNF-alpha signaling, indicating that TLR1 operated at a step upstream of the convergence between the two pathways. Inhibition of TLR4 signaling was mediated by the extracellular, but not cytoplasmic domain of TLR1. In addition, TLR1 physically associated with TLR4 in co-precipitation experiments. These findings suggest that TLR1 might restrain potentially dangerous innate response to LPS by binding to TLR4 and preventing the formation of active signaling complexes.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda 20892-1360, USA.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Spitzer
authors.forename: Alberto
authors.initials: A
authors.lastname: Visintin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mazzoni
authors.forename: Margaret N
authors.initials: MN
authors.lastname: Kennedy
authors.forename: David M
authors.initials: DM
authors.lastname: Segal
mesh_terms: D002460:Cell Line; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D029721:Drosophila Proteins; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051194:Toll-Like Receptor 1; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
chemical_list: D029721:Drosophila Proteins; D008070:Lipopolysaccharides; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; C495345:TLR4 protein, human; D051194:Toll-Like Receptor 1; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha