title: Cytokine-induced monocyte adhesion to endothelial cells involves platelet-activating factor: suppression by conjugated linoleic acid.
abstract: Monocyte-endothelium interaction is key to many acute and chronic inflammatory diseases. We have investigated the factors regulating monocyte attachment to cytokine-activated human umbilical vein endothelial cells (HUVEC) and the modulatory effect of the polyunsaturated fatty acid (PUFA), conjugated linoleic acid (CLA) in this process. Both TNF-alpha and IL-1beta induced HUVEC platelet-activating factor (PAF) production and PAF was required for subsequent firm THP-1 monocyte adhesion since it was inhibited by both PAF receptor antagonists (BN-52021 or CV-6209) and a PAF synthesis inhibitor (sanguinarine). CLA inhibited the binding of both THP-1 and isolated human peripheral blood monocytes to HUVEC by up to 40% with the CLA t10,c12 isomer suppressing adhesion dose-dependently. Investigation into the mechanism involved demonstrated that with IL-1beta, VCAM-1 and ICAM-1 levels and pro-inflammatory cytokine expression were largely unaffected by CLA. Through the use of PAF receptor antagonists and PAF synthesis inhibitors, CLA was shown to inhibit cytokine-induced binding by suppressing PAF production. Direct assay of PAF levels confirmed this result. We conclude that endothelial-generated PAF plays a central role in cytokine-induced monocyte adherence to endothelium and that the anti-inflammatory action of PUFAs such as CLA in suppressing monocyte-endothelial interaction is mediated through attenuation of pro-inflammatory phospholipids such as PAF.
authors.affiliation: Lipid and Redox Regulation Group, Vascular Health Programme, Rowett Research Institute, Bucksburn, Aberdeen AB21 9SB, UK. A.Sneddon@rowett.ac.uk
authors.forename: Alan A
authors.initials: AA
authors.lastname: Sneddon
authors.forename: Ewan
authors.initials: E
authors.lastname: McLeod
authors.forename: Klaus W J
authors.initials: KW
authors.lastname: Wahle
authors.forename: John R
authors.initials: JR
authors.lastname: Arthur
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002478:Cells, Cultured; D004224:Diterpenes / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D046934:Ginkgolides; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007375:Interleukin-1 / Q000494:pharmacology; D007783:Lactones / Q000494:pharmacology; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000502:physiology*; D010972:Platelet Activating Factor / Q000096:biosynthesis*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors; D011726:Pyridinium Compounds / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
chemical_list: D004224:Diterpenes; D046934:Ginkgolides; D007375:Interleukin-1; D007783:Lactones; D044243:Linoleic Acids, Conjugated; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011726:Pyridinium Compounds; D043562:Receptors, G-Protein-Coupled; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C039351:platelet activating factor receptor; C053321:CV 6209; D018799:Intercellular Adhesion Molecule-1; C045856:ginkgolide B