title: Activation of endothelial TLR2 by bacterial lipoprotein upregulates proteins specific for the neutrophil response.
abstract: The vascular endothelium is integrally involved in the host response to infection and in organ failure during acute inflammatory disorders such as sepsis. Gram-negative and Gram-positive bacterial lipoproteins circulate in sepsis and can directly activate the endothelium by binding to endothelial cell (EC) TLR2. In this report, we perform the most comprehensive analysis to date of the immune-related genes regulated after activation of endothelial TLR2 by bacterial di- and triacylated lipopeptides. We found that TLR2 activation specifically induces the expression of the genes IL-6, IL-8, CSF2, CSF3, ICAM1 and SELE by human umbilical vein ECs and human lung microvascular ECs. These proteins participate in neutrophil recruitment, adherence and activation at sites of inflammation. Significantly, our studies demonstrate that TLR2-mediated EC responses are specifically geared towards recruitment, activation, and survival of neutrophils and not mononuclear leukocytes, that ECs do not require priming by other inflammatory stimuli to respond to bacterial lipopeptides and, unlike mononuclear leukocytes, TLR2 agonists do not induce ECs to secrete TNF-α. This study suggests that endothelial TLR2 may be an important regulator of neutrophil trafficking to sites of infection in general, and that direct activation of lung endothelial TLR2 may contribute to acute lung injury during sepsis.
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA 94143, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilhelmsen
authors.forename: Kailin R
authors.initials: KR
authors.lastname: Mesa
authors.forename: Arun
authors.initials: A
authors.lastname: Prakash
authors.forename: Fengyun
authors.initials: F
authors.lastname: Xu
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
mesh_terms: D001426:Bacterial Proteins / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology*; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008074:Lipoproteins / Q000494:pharmacology; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics; D018805:Sepsis / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D001426:Bacterial Proteins; D016207:Cytokines; D019040:E-Selectin; C573420:ICAM1 protein, human; D008074:Lipoproteins; D034741:RNA, Small Interfering; C546936:SELE protein, human; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; C061108:N-palmitoyl-S-(2,3-bis(palmitoyloxy)propyl)cysteinyl-seryl-lysyl-lysyl-lysyl-lysine; D018799:Intercellular Adhesion Molecule-1; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor