title: Poly ADP ribose-polymerase inhibitors prevent the upregulation of ICAM-1 and E-selectin in response to Th1 cytokine stimulation.
abstract: We studied the role of poly-ADP-ribose polymerase (PARP) in the mobilization of ICAM-1, VCAM-1, and E-selectin by TNF-alpha and IL-1beta in cultured human endothelial cells. Enzyme linked immunosorbent analysis (ELISA) was used to assess if ICAM-1, VCAM-1, and E-selectin were expressed at the cell surface, and if PARP inhibition (using the selective PARP inhibitor GPI 6150) blocked the induced expression. Endothelial cell adhesion molecule expression was evaluated at 4 and at 24 h after cytokine stimulation. At 4 h ICAM-1 and E-selectin, but not VACM-1, were stimulated by both IL-1beta and TNF-alpha. Blocking PARP via GPI 6150 only affected TNF-alpha induced E-selectin expression at 4 hours. ICAM-1, VCAM-1, and E-selectin expression were all stimulated by both IL-1beta and TNF-alpha in the 24 h assays. PARP inhibition with GPI 6150 blocked the IL-1beta mediated stimulation of both ICAM-1 and E-selectin expression, and blocked TNF-alpha stimulation of ICAM-1 expression at 24 h. These experiments suggest that specific PARP inhibition may provide a novel method of controlling leukocyte dependent inflammation through the reduction of ICAM-1 and E-selectin expression in endothelial cells in response to cytokines.
authors.affiliation: LSU Health Sciences Center, Shreveport, Louisiana 71130-3932, USA.
authors.forename: C
authors.initials: C
authors.lastname: Sharp
authors.forename: A
authors.initials: A
authors.lastname: Warren
authors.forename: T
authors.initials: T
authors.lastname: Oshima
authors.forename: L
authors.initials: L
authors.lastname: Williams
authors.forename: J H
authors.initials: JH
authors.lastname: Li
authors.forename: J S
authors.initials: JS
authors.lastname: Alexander
mesh_terms: D001578:Benzopyrans / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D019040:E-Selectin / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000517:prevention & control; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D018417:Th1 Cells / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D016207:Cytokines; D019040:E-Selectin; D004791:Enzyme Inhibitors; C417259:GPI 6150; D007375:Interleukin-1; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1