title: The CD14 ligands lipoarabinomannan and lipopolysaccharide differ in their requirement for Toll-like receptors.
abstract: Mammalian Toll-like receptor (TLR) proteins are new members of the IL-1 receptor family that participate in activation of cells by bacteria and bacterial products. Several recent reports indicate that TLR proteins mediate cellular activation by bacterial LPS via a signaling pathway that is largely shared by the type I IL-1 receptor. We previously showed that Chinese hamster ovary (CHO) fibroblasts engineered to express CD14 (CHO/CD14) were responsive to LPS, but not to a distinct CD14 ligand, mycobacterial lipoarabinomannan (LAM). These CHO/CD14 cells were subsequently found to possess a frame-shift mutation within the TLR2 gene which resulted in their inability to express functional TLR2 protein. Thus, we hypothesized that TLR2, but not TLR4, was necessary for LAM signaling. In this paper we show that CHO/CD14 cells engineered to express functional TLR2 protein acquired the ability to be activated by LAM. Similarly, overexpression of TLR2 in murine macrophages conferred enhanced LAM responsiveness. Together, our data demonstrate that the distinct CD14 ligands LAM and LPS utilize different TLR proteins to initiate intracellular signals. These findings suggest a novel receptor signaling paradigm in which the binding of distinct ligands is mediated by a common receptor chain, but cellular activation is initiated via distinct signal-transducing chains that confer ligand specificity. This paradigm contrasts with many cytokine receptor complexes in which receptor specificity is conferred by a unique ligand-binding chain but cellular activation is initiated via shared signal-transducing chains.
authors.affiliation: The Pulmonary Center, Boston University School of Medicine, MA 02118, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Means
authors.forename: E
authors.initials: E
authors.lastname: Lien
authors.forename: A
authors.initials: A
authors.lastname: Yoshimura
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: D T
authors.initials: DT
authors.lastname: Golenbock
authors.forename: M J
authors.initials: MJ
authors.lastname: Fenton
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D017124:Conserved Sequence; D006224:Cricetinae; D029721:Drosophila Proteins; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008809:Mice, Inbred C3H; D016328:NF-kappa B / Q000235:genetics; D010446:Peptide Fragments / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D010957:Plasmids / Q000138:chemical synthesis / Q000502:physiology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D015533:Transcriptional Activation / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D029721:Drosophila Proteins; D008024:Ligands; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C050016:lipoarabinomannan