A20 inhibits NF-κB activation in endothelial cells without sensitizing to tumor necrosis factor-mediated apoptosis

Abstract

Expression of the NF-KB-dependent gene A2O in endothelial calls (EC) inhibits tumor necrosis factor (TNF)-mediated apoptosis in the presence of cycloheximide end acts upstream of IκBα degradation to block activation of NF-κB. Although inhibition of NF-κB by IκBα renders cells susceptible to TNF-induced apoptosis, we show that when A20 and IκBα are coexpressed, the effect of A20 predominates in that EC are rescued from TNF-mediated apoptosis. These findIngs place A20 in the category of 'protective' genes that are induced in response to inflammatory stimuli to protect EC from unfettered activation and from undergoing apoptosis even when NF-κB is blocked. From a therapeutic perspective, genetic engineering of EC to express an NF-κB inhibitor such as A20 offers the mean of achieving an anti- inflammatory effect without sensitizing the cells to TNF-mediated apoptosis.