CHEMOKINE RECEPTORS IN HUMAN ENDOTHELIAL-CELLS - FUNCTIONAL EXPRESSION OF CXCR4 AND ITS TRANSCRIPTIONAL REGULATION BY INFLAMMATORY CYTOKINES

Chemokines play an important role in the regulation of endothelial cel l (EC) function, including proliferation, migration and differentiatio n during angiogenesis, and re-endothelialization after injury. In this study, reverse transcriptase-polymerase chain reaction was used to re veal expression of various CXC and CC chemokine receptors in human umb ilical vein EC, Northern analysis showed. that CXCR4 was selectively e xpressed in vascular EC, but not in smooth muscle cells. Compared with other chemokines, stromal cell derived factor-1 alpha (SDF-1 alpha), the known CXCR4 ligand, was an efficacious chemoattractant. for EC, ca using the migration of similar to 40% input cells with an EC50 of 10-2 0 nM., Of the chemokines tested, only SDF-1 alpha induced a rapid, tho ugh variable mobilization of intracellular Ca2+ in EC. Experiments wit h actinomycin D demonstrated that CXCR4 transcripts were short-lived, indicating a rapid mRNA turnover. Interferon-gamma (IFN-gamma) caused a pronounced downregulation of CXCR4 mRNA in a concentration-and time- dependent manner, In a striking functional correlation, IFN-gamma trea tment also attenuated the chemotactic response of EC to SDF-1 alpha, I L-1 beta, tumor necrosis factor-al and lipopolysaccharide produced a t ime course-dependent biphasic effect on CXCR4 transcription Expression of CXCR4 in EC is significant, more so as it and several CC chemokine receptors have been shown to serve as fusion ca-receptors along with CD4 during human immunodeficiency virus infection. Taken together, the se findings provide evidence of chemokine receptor expression in EC an d offer an explanation for the action of chemokines like SDF-1 alpha o n the vascular endothelium.