title: Influence of proinflammatory stimuli on the expression of vascular ribonuclease 1 in endothelial cells.
abstract: Extracellular RNA (eRNA) released under injury or pathological conditions has been identified as a yet unrecognized vascular alarm signal to induce procoagulant, permeability-promoting, and proinflammatory activities. eRNA-induced functions were largely prevented by administration of RNase1 as a natural blood vessel-protective antagonist of eRNA. The aim of this study was to investigate the inflammatory regulation of endothelial cell RNase1, which is partly stored in Weibel-Palade bodies of these cells. Long-term treatment of human umbilical vein endothelial cells (HUVECs) with inflammatory agents like tumor necrosis factor α (TNF-α) or interleukin 1β (IL-1β), but not with eRNA, significantly decreased the release (34 ± 5%; 34 ± 7% of control) as well as the cellular expression (19.5 ± 5%; 33 ± 8% of control) of RNase1. Down-regulation of RNase1 by TNF-α stimulation or RNase1 siRNA knockdown increased the permeability of HUVEC monolayers, demonstrated by dearrangement of VE-cadherins at cell-cell borders. Mechanistically, cytokine-induced decrease of RNase1 expression did not involve the nuclear factor κ B (NFκB) signaling pathway but epigenic modifications. Since inhibition of histone deacetylases resulted in recovery of RNase1 expression and secretion after cytokine treatment, an acetylation-dependent process of RNase1 regulation is proposed. These results indicate that cytokine-mediated down-regulation of RNase1 in endothelial cells may aggravate eRNA-induced inflammatory activities and thereby disturbs the vascular homeostasis of the extracellular RNA/RNase system.
authors.affiliation: 1Institute for Biochemistry, Medical School, Justus-Liebig-University, Friedrichstrasse 24, 35392 Giessen, Germany. silvia.fischer@biochemie.med.uni-giessen.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Gansler
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Silvia
authors.initials: S
authors.lastname: Fischer
mesh_terms: D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D008856:Microscopy, Fluorescence; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; D012260:Ribonucleases
keywords: extracellular RNA; tumor necrosis factor α, vascular homeostasis