TNF alpha down-regulates CD105 expression in vascular endothelial cells: A comparative study with TGF beta 1

The vascular endothelium participates in angiogenesis, inflammation and the immune response, which are modulated by vasoactive cytokines such as tumour necrosis factor-alpha (TNFalpha) and transforming growth factor-beta1 (TGFbeta1). CD105 is a component of the TGFbeta receptor complex and is abundantly expressed in activated/injured endothelium where it is implicated in multiple cellular processes. Up-regulation of CD105 in synovial cells of rheumatoid arthritis and psoriatic lesions implies a possible role in the pathogenesis of such inflammatory disorders. The pro-inflammatory cytokine, TNFalpha, and anti-inflammatory cytokine, TGFbeta1, regulate multiple cellular processes such as proliferation, differentiation and apoptosis. Our hypothesis is that CD105 gene expression in endothelial cells is regulated by the multifunctional cytokines TNFalpha and TGFbeta1. By using human dermal microvascular endothelial cells the present study has shown that long-term treatment with TNFa (0.1-5 ng/ml) elicited a concentration-and time-dependent significant suppression (over 50% reduction) in CD105 protein levels. The observations that no significant alterations in the CD105 mRNA levels or in the CD105 promoter activity were found and that the potent inhibitor of NFKB, PDTC, did not affect the TNFalpha action suggest that CD105 down-regulation by TNFalpha is not at the transcriptional level. In contrast to TNFalpha, TGFbeta1 significantly elevated CD105 protein and mRNA erpression (approximate to2-fold increase) through activation of its promoter activity. From these data we conclude that TNFalpha and TGFbeta1 exert opposing effects on CD105 expression in human vascular endothelial cells and that CD105 is enmeshed in the network of signal pathways modulating multiple cellular functions.OncologySCI(E)17ARTICLE2B1189-11962