title: Chylomicrons combined with endotoxin moderate microvascular permeability.
abstract: Triglyceride-rich lipoprotein-bound endotoxin (CM-LPS) inhibits the host innate immune response to sepsis by attenuating the hepatocellular response to pro-inflammatory cytokine stimulation. This 'cytokine tolerance' in hepatocytes is a transient, receptor-dependent process that correlates with internalization of CM-LPS via low density lipoprotein (LDL) receptors. Since endothelial cells are integral to the immune response and similarly express LDL receptors, we hypothesized that CM-LPS could be internalized and ultimately attenuate the deleterious effects of pro-inflammatory molecules like tumor necrosis factor-α (TNF-α) and platelet activating factor (PAF) on endothelial permeability. Here, we show that CM-LPS complexes induce cytokine tolerance in endothelial cells. In rats, TNF-α increased hydraulic conductivity 2.5-fold over baseline and PAF increased it 5-fold; but, pretreatment with CM-LPS or an attenuated analog (CM-LPS*) inhibited these changes. Nuclear/cytoplasmic levels of p65 were reduced after TNF-α-stimulation in endothelial cell monolayers pretreated with CM-LPS, a finding consistent with inhibition of nuclear factor (NF)-κB translocation. Also consistent with inhibition was stabilized intercellular adhesion, as illustrated with antibody to VE-cadherin using confocal microscopy. These results provide additional support for the integral role of lipoproteins in the innate immune response to infection and lend further credence to developing lipid-based therapy for Gram-negative sepsis.
authors.affiliation: University of California Surgical Research Laboratory at San Francisco General Hospital, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0104, USA.
authors.forename: Austin L
authors.initials: AL
authors.lastname: Spitzer
authors.forename: Kelley I
authors.initials: KI
authors.lastname: Chuang
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Victorino
authors.forename: Behzad
authors.initials: B
authors.lastname: Kasravi
authors.forename: Brian
authors.initials: B
authors.lastname: Curran
authors.forename: Diana
authors.initials: D
authors.lastname: Lee
authors.forename: Hobart W
authors.initials: HW
authors.lastname: Harris
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015820:Cadherins / Q000276:immunology / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002914:Chylomicrons / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004731:Endotoxins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000276:immunology*; D007113:Immunity, Innate; D007165:Immunosuppression Therapy; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D002914:Chylomicrons; D004731:Endotoxins; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019892:eIF-2 Kinase; D000099152:Cadherin 5