Influence of proinflammatory stimuli on the expression of vascular ribonuclease 1 in endothelial cells

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 (TNF-) or interleukin 1 (IL-1), 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- 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 B (NFB) 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.Gansler, J., Preissner, K. T., Fischer, S. Influence of proinflammatory stimuli on the expression of vascular ribonuclease 1 in endothelial cells.