GLUCOCORTICOID-MEDIATED REPRESSION OF NF-KAPPA-B ACTIVITY IN ENDOTHELIAL-CELLS DOES NOT INVOLVE INDUCTION OF I-KAPPA-B-ALPHA SYNTHESIS

Repression of NF kappa B-dependent gene expression is one of the major elements of immunosuppression by glucocorticoids. Protein-protein int eractions between the glucocorticoid receptor and NF kappa B have been characterized and shown to be a possible mechanism of mutual inhibiti on of transactivation properties, More recently, glucocorticoid-mediat ed induction of I kappa B alpha, an inhibitor of NF kappa B, has been described in monocytes and lymphocytes; an increase in I kappa B alpha mRNA and protein resulted in inactivation and cytosolic retention of NF kappa B, Thus, rather than the physical interaction between the glu cocorticoid receptor and NF kappa B, the up-regulation of I kappa B al pha was presented as the key element in immunosuppression by glucocort icoids. in contrast, we show that the I kappa B alpha pathway is not i nvolved in glucocorticoid-mediated inhibition of NF kappa B activity i n endothelial cells, Although transcriptional activation by NF kappa B was significantly reduced in the presence of glucocorticoids, we did not detect induction of I kappa B alpha protein that could prevent nuc lear translocation of NF kappa B upon stimulation with lipopolysacchar ide or tumor necrosis factor alpha, Furthermore, treatment with glucoc orticoids did not seem to affect the transcription rate or mRNA stabil ity of I kappa B alpha. Ne therefore conclude that, although induction of I kappa B alpha expression by glucocorticoids seems to be of impor tance in monocytes and lymphocytes, it cannot explain inhibition of NF kappa B-dependent gene expression in endothelial cells. Our results e mphasize the relevance of physical interaction between the glucocortic oid receptor and NF kappa B in endothelial cells and thus in suppressi on of inflammation by glucocorticoids.