title: Upregulation of TNF-alpha-induced ICAM-1 surface expression by adenylate cyclase-dependent pathway in human endothelial cells.
abstract: The level of adhesion molecules expressed at the endothelial cell surface is critical in the control of inflammation. Adenylate cyclase (AC) activity allowing cyclic adenosine monophosphate (cAMP) production can modulate the inflammatory process. We investigated the AC-dependent modulation of ICAM-1 surface expression in human umbilical venous endothelial cells (HUVEC). Pretreatment of HUVEC with forskolin significantly upregulated tumor necrosis factor alpha (TNF-alpha)- and interleukin-1 alpha (IL1-alpha)-induced ICAM-1 surface expression exclusively after a prolonged time of incubation with forskolin (at least 7-8 h). A poorly metabolizable analog of cAMP, dibutyryl-cAMP, mimicked forskolin effect on ICAM-1 surface expression. Protein kinase A (PKA) inhibitor H89 prevented forskolin effect on ICAM-1 surface expression. Upregulation of ICAM-1 surface level occurred through the increase in its mRNA levels and also to a subsequent activation of ICAM-1 intracellular trafficking towards cell surface. Stimulation by agonists of beta-adrenergic receptors did not alter the TNF-alpha-induced ICAM-1 surface expression. Pretreatment of HUVEC with pertussis toxin, which is known to activate AC through Gialpha inhibition, upregulated mRNA levels and surface expression of ICAM-1 induced by TNF-alpha. This effect was serum-dependent, since ICAM-1 expression was no more upregulated by pertussis toxin in cells cultured in 1% instead of 20% serum-enriched medium. However, forskolin treatment of HUVEC did not modify their overall adhesive properties. In conclusion, a persistent cAMP level elevation activating PKA is able to enhance ICAM-1 expression at the cell surface of endothelial cells placed under pro-inflammatory conditions. Combination of activation of gene transcription and membrane targeting may account for this augmentation.
authors.affiliation: Inserm UMR626, IPHM, Faculté de Médecine Timone, Marseille Cedex, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Bernot
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
authors.forename: Matthias
authors.initials: M
authors.lastname: Canault
authors.forename: Irène
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: Gilles
authors.initials: G
authors.lastname: Nalbone
mesh_terms: D000262:Adenylyl Cyclases / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000037:antagonists & inhibitors; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000262:Adenylyl Cyclases