title: Pathogen recognition by Toll-like receptor 2 activates Weibel-Palade body exocytosis in human aortic endothelial cells.
abstract: The endothelial cell-specific granule Weibel-Palade body releases vasoactive substances capable of modulating vascular inflammation. Although innate recognition of pathogens by Toll-like receptors (TLRs) is thought to play a crucial role in promotion of inflammatory responses, the molecular basis for early-phase responses of endothelial cells to bacterial pathogens has not fully been understood. We here report that human aortic endothelial cells respond to bacterial lipoteichoic acid (LTA) and synthetic bacterial lipopeptides, but not lipopolysaccharide or peptidoglycan, to induce Weibel-Palade body exocytosis, accompanied by release or externalization of the storage components von Willebrand factor and P-selectin. LTA could activate rapid Weibel-Palade body exocytosis through a TLR2- and MyD88-dependent mechanism without de novo protein synthesis. This process was at least mediated through MyD88-dependent phosphorylation and activation of phospholipase Cgamma. Moreover, LTA activated interleukin-1 receptor-associated kinase-1-dependent delayed exocytosis with de novo protein synthesis and phospholipase Cgamma-dependent activation of the NF-kappaB pathway. Increased TLR2 expression by transfection or interferon-gamma treatment increased TLR2-mediated Weibel-Palade body exocytosis, whereas reduced TLR2 expression under laminar flow decreased the response. Thus, we propose a novel role for TLR2 in induction of a primary proinflammatory event in aortic endothelial cells through Weibel-Palade body exocytosis, which may be an important step for linking innate recognition of bacterial pathogens to vascular inflammation.
authors.affiliation: Department of Oral Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. into@nils.go.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Into
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kanno
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Dohkan
authors.forename: Misako
authors.initials: M
authors.lastname: Nakashima
authors.forename: Megumi
authors.initials: M
authors.lastname: Inomata
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Shibata
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lowenstein
authors.forename: Kenji
authors.initials: K
authors.lastname: Matsushita
mesh_terms: D001011:Aorta / Q000166:cytology*; D002460:Cell Line; D002473:Cell Wall / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000382:microbiology*; D005089:Exocytosis; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D011485:Protein Binding; D013682:Teichoic Acids / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020302:Weibel-Palade Bodies / Q000378:metabolism / Q000382:microbiology*
chemical_list: D008070:Lipopolysaccharides; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D007371:Interferon-gamma