A dual mechanism mediates repression of NF-κB activity by glucocorticoids

Repression of nuclear factor (NF)-kappa B-dependent gene expression is one of the key characteristics by which glucocorticoids exert their antiinflammatory and immunosuppressive effects. In vitro studies have shown protein-protein interactions between NF-kappa B and the glucocorticoid receptor, possibly explaining their mutual repression of transcriptional activity. Furthermore, glucocorticoid-induced transcription of I kappa B alpha was presented as a mechanism in mediation of immunosuppression by glucocorticoids. At present, the relative contribution of each mechanism has not been investigated, We show that dexamethasone induced I kappa B alpha gene transcription in human pulmonary epithelial A549 cells, However, this enhanced I kappa B alpha synthesis did not cause repression of NF-kappa B DNA-binding activity. In addition, dexamethasone was still able to inhibit the expression of NF-kappa B target genes (cyclooxygenase-2, intercellular adhesion molecule-1) in the absence of protein synthesis. Furthermore, we show that the antihormone RU486 did not induce I kappa B alpha expression, However, RU486 was still able to induce, albeit less efficiently, both glucocorticoid-and progesterone receptor-mediated repression of endogenous NF-kappa B target gene expression in A549 cells and the breast cancer cell line T47D, respectively. Taken together, these results indicate that induced I kappa B alpha expression accounts for only part of the repression of NF-kappa B activity by glucocorticoids and progestins. In addition, protein-protein interactions between NF-kappa B and the glucocorticoid or progesterone receptor, resulting in repression of NF-kappa B activity, seem also to be involved. We therefore conclude that NF-kappa B activity is repressed via a dual mechanism involving both protein-protein interactions and induction of I kappa B alpha.