title: TIRAP mediates endotoxin-induced NF-kappaB activation and apoptosis in endothelial cells.
abstract: Bacterial lipopolysaccharide (LPS) initiates multiple signaling events in vascular endothelial cells that can result in activation and/or cell death. LPS-induced activation of endothelial cells elicits a wide array of vascular endothelial responses, many of which are dependent on NF-kappaB activation. Several of the signaling molecules that mediate LPS-induced NF-kappaB activation, including Tlr-4, MyD88, and IRAK-1, have been similarly reported to mediate LPS pro-apoptotic signaling. Recently, a new signaling molecule, TIRAP, has been identified that mediates LPS-induced NF-kappaB signaling in monocytes and macrophages. Using a TIRAP dominant negative construct, we have identified a role for TIRAP in mediating LPS-induced NF-kappaB activation and apoptosis in human endothelial cells. These data identify TIRAP as a dual functioning signaling molecule and suggest the presence of a MyD88-independent LPS signaling pathway in human endothelial cells.
authors.affiliation: Department of Surgery, University of Washington School of Medicine, Seattle, WA 98104, USA. dbannerm@u.washington.edu
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Bannerman
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Erwert
authors.forename: Robert K
authors.initials: RK
authors.lastname: Winn
authors.forename: John M
authors.initials: JM
authors.lastname: Harlan
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008562:Membrane Glycoproteins; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human