title: Bacterial lipoprotein TLR2 agonists broadly modulate endothelial function and coagulation pathways in vitro and in vivo.
abstract: TLR2 activation induces cellular and organ inflammation and affects lung function. Because deranged endothelial function and coagulation pathways contribute to sepsis-induced organ failure, we studied the effects of bacterial lipoprotein TLR2 agonists, including peptidoglycan-associated lipoprotein, Pam3Cys, and murein lipoprotein, on endothelial function and coagulation pathways in vitro and in vivo. TLR2 agonist treatment induced diverse human endothelial cells to produce IL-6 and IL-8 and to express E-selectin on their surface, including HUVEC, human lung microvascular endothelial cells, and human coronary artery endothelial cells. Treatment of HUVEC with TLR2 agonists caused increased monolayer permeability and had multiple coagulation effects, including increased production of plasminogen activator inhibitor-1 (PAI-1) and tissue factor, as well as decreased production of tissue plasminogen activator and tissue factor pathway inhibitor. TLR2 agonist treatment also increased HUVEC expression of TLR2 itself. Peptidoglycan-associated lipoprotein induced IL-6 production by endothelial cells from wild-type mice but not from TLR2 knockout mice, indicating TLR2 specificity. Mice were challenged with TLR2 agonists, and lungs and plasmas were assessed for markers of leukocyte trafficking and coagulopathy. Wild-type mice, but not TLR2 mice, that were challenged i.v. with TLR2 agonists had increased lung levels of myeloperoxidase and mRNAs for E-selectin, P-selectin, and MCP-1, and they had increased plasma PAI-1 and E-selectin levels. Intratracheally administered TLR2 agonist caused increased lung fibrin levels. These studies show that TLR2 activation by bacterial lipoproteins broadly affects endothelial function and coagulation pathways, suggesting that TLR2 activation contributes in multiple ways to endothelial activation, coagulopathy, and vascular leakage in sepsis.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Hae-Sook
authors.initials: HS
authors.lastname: Shin
authors.forename: Fengyun
authors.initials: F
authors.lastname: Xu
authors.forename: Aranya
authors.initials: A
authors.lastname: Bagchi
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Herrup
authors.forename: Arun
authors.initials: A
authors.lastname: Prakash
authors.forename: Catherine
authors.initials: C
authors.lastname: Valentine
authors.forename: Hrishikesh
authors.initials: H
authors.lastname: Kulkarni
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilhelmsen
authors.forename: Shaw
authors.initials: S
authors.lastname: Warren
authors.forename: Judith
authors.initials: J
authors.lastname: Hellman
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000819:agonists / Q000494:pharmacology / Q000502:physiology*; D001777:Blood Coagulation / Q000276:immunology*; D002199:Capillary Permeability / Q000276:immunology; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D029968:Escherichia coli Proteins / Q000819:agonists / Q000502:physiology*; D006801:Humans; D016130:Immunophenotyping; D008074:Lipoproteins / Q000819:agonists / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010457:Peptidoglycan / Q000494:pharmacology*; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000172:deficiency / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000925:Anticoagulants; D029968:Escherichia coli Proteins; D008074:Lipoproteins; D010457:Peptidoglycan; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C051928:lipoprotein-associated coagulation inhibitor