title: Altered adhesive properties of cord blood endothelial outgrowth cells expressing IL-1ra.
abstract: The aim of this study was to examine the potential of endothelial outgrowth cells (EOCs) expanded from CD34(+) cord blood-derived cells (CB-EOCs) for overexpression of therapeutic transgenes. As proof of principle, we overexpressed icIL-1ra in CB-EOCs. Proinflammatory activation of CB-EOCs in response to cytokine stimulation (IL-1beta and tumor necrosis factor (TNF)) and during coculture with monocytes showed that icIL-1ra-expressing CB-EOCs express significantly reduced levels of ICAM-1, MCP-1 and thrombin receptor expression. Moreover, overexpression of icIL-1ra attenuated the IL-1beta-mediated proinflammatory activation by diminishing the expression of ICAM-1, SELE, MCP-1 and IL-1beta. Interestingly, overexpression of icIL-1ra also inhibited TNF-induced upregulation of ICAM-1. Expression of ICAM-1, VCAM-1, tissue factor and IL-1beta was also decreased on direct contact with monocytes. These changes in gene expression were accompanied by functional reduction in leukocyte rolling, adhesion of monocytes to CB-EOCs, as well as by a reduction in transendothelial migration of monocytes. Our findings show that CB-EOCs stably expressing transgenic icIL-1ra are protected against activation by not only IL-1beta but also TNFalpha-mediated proinflammatory stimuli and inhibit decisive pathomechanisms of inflammatory processes such as rolling, adhesion and transmigration of monocytes. Therefore, icIL-ra transgenic CB-EOCs may prove to be beneficial in the treatment of IL-1beta- and TNFalpha-mediated inflammatory vasculopathies.
authors.affiliation: III. Medizinische Klinik, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Fischer
authors.forename: Marc
authors.initials: M
authors.lastname: Rümmler
authors.forename: Christian
authors.initials: C
authors.lastname: Schulz
authors.forename: Christian
authors.initials: C
authors.lastname: Peschel
authors.forename: Ilka
authors.initials: I
authors.lastname: Ott
authors.forename: Robert A J
authors.initials: RA
authors.lastname: Oostendorp
mesh_terms: D000818:Animals; D018952:Antigens, CD34; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000276:immunology; D019040:E-Selectin / Q000096:biosynthesis / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D005312:Fetal Blood / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000276:immunology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000096:biosynthesis / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D018179:Receptors, Thrombin / Q000096:biosynthesis / Q000276:immunology; D014161:Transduction, Genetic; D019076:Transgenes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology; D014652:Vascular Diseases / Q000276:immunology / Q000628:therapy
chemical_list: D018952:Antigens, CD34; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D019040:E-Selectin; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D018179:Receptors, Thrombin; C546936:SELE protein, human; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1