Glucocorticoid-mediated Repression of NFκB Activity in Endothelial Cells Does Not Involve Induction of IκBα Synthesis*

Repression of NFκB-dependent gene expression is one of the major elements of immunosuppression by glucocorticoids. Protein-protein interactions between the glucocorticoid receptor and NFκB have been characterized and shown to be a possible mechanism of mutual inhibition of transactivation properties. More recently, glucocorticoid-mediated induction of IκBα, an inhibitor of NFκB, has been described in monocytes and lymphocytes; an increase in IκBα mRNA and protein resulted in inactivation and cytosolic retention of NFκB. Thus, rather than the physical interaction between the glucocorticoid receptor and NFκB, the up-regulation of IκBα was presented as the key element in immunosuppression by glucocorticoids. In contrast, we show that the IκBα pathway is not involved in glucocorticoid-mediated inhibition of NFκB activity in endothelial cells. Although transcriptional activation by NFκB was significantly reduced in the presence of glucocorticoids, we did not detect induction of IκBα protein that could prevent nuclear translocation of NFκB upon stimulation with lipopolysaccharide or tumor necrosis factor α. Furthermore, treatment with glucocorticoids did not seem to affect the transcription rate or mRNA stability of IκBα. We therefore conclude that, although induction of IκBα expression by glucocorticoids seems to be of importance in monocytes and lymphocytes, it cannot explain inhibition of NFκB-dependent gene expression in endothelial cells. Our results emphasize the relevance of physical interaction between the glucocorticoid receptor and NFκB in endothelial cells and thus in suppression of inflammation by glucocorticoids.