Interferon-alpha prevents apoptosis of endothelial cells after short-term exposure but induces replicative senescence after continuous stimulation.
Although the antiangiogenic activity of type I interferons (IFN) is well known, the mechanism by which it occurs is unclear. In the present study, we have investigated effects of short-term and long-term IFN-alpha exposure on different types of endothelial cells (EC). Short-term IFN-alpha treatment resulted in a distinct reduction of apoptosis of serum and growth factor starved HUVEC and HDMEC. This was accompanied by a strong upregulation of the IFN inducible guanylate binding protein-1 (GBP-1) whereas no consistent regulation of several known antiapoptotic proteins was evident. Stable transfection of HUVEC with an expression vector for GBP-1 mimicked the protective effect of IFN-alpha, suggesting that GBP-1 may contribute to the inhibition of apoptosis. When IFN-alpha, together with serum and EC growth factors, was present continuously a decrease of population doublings by more than 40% was observed in both HDMEC and HCAEC. In addition, the cells displayed a senescent phenotype significantly earlier than control cells and showed an increased adherence for monocytes. Our findings suggest that the antiangiogenic effect of IFN-alpha is mediated by inducing EC senescence rather than EC apoptosis. Furthermore IFN-alpha released in chronic inflammatory conditions might contribute via its prosenescent activity to the pathogenesis of atherosclerosis.
Pammer
Johannes
J
Institute of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
Reinisch
Christine
C
Birner
Peter
P
Pogoda
Kristin
K
Sturzl
Michael
M
Tschachler
Erwin
E
D017209:Apoptosis / Q000276:immunology*; D050197:Atherosclerosis / Q000276:immunology; D002196:Capillaries / Q000166:cytology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000276:immunology*; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000276:immunology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism*; D016898:Interferon-alpha / Q000276:immunology*; D009389:Neovascularization, Pathologic / Q000276:immunology; D014471:Umbilical Veins / Q000166:cytology; D015854:Up-Regulation
C490287:GBP1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016898:Interferon-alpha; D019204:GTP-Binding Proteins