The helical domain of GBP-1 mediates the inhibition of endothelial cell proliferation by inflammatory cytokines

Inflammatory cytokines (IC) activate endothelial cell adhesiveness for mono cytes and inhibit endothelial cell growth. Here we report the identificatio n of the human guanylate binding protein-1 (GBP-1) as the key and specific mediator of the anti-proliferative effect of IC on endothelial cells. GBP-1 expression was induced by IC, downregulated by angiogenic growth factors, and inversely related to cell proliferation both in vitro in microvascular and macrovascular endothelial cells and in vivo in vessel endothelial cells of Kaposi's sarcoma. Experimental modulation of GBP-1 expression demonstra ted that GBP-1 mediates selectively the anti-proliferative effect of IC, wi thout affecting endothelial cell adhesiveness for monocytes. GBP-1 anti-pro liferative activity did not affect ERK-1/2 activation, occurred in the abse nce of apoptosis, was found to be independent of the GTPase activity and is oprenylation of the molecule, but was specifically mediated by the C-termin al helical domain of the protein. These results define GBP-1 as an importan t tool for dissection of the complex activity of IC on endothelial cells, a nd detection and specific modulation of the IC-activated non-proliferating phenotype of endothelial cells in vascular diseases.