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

Abstract

Repression of nuclear factor (NF)-κB-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-κB and the glucocorticoid receptor, possibly explaining their mutual repression of transcriptional activity. Furthermore, glucocorticoid-induced transcription of IκBα 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 IκBα gene transcription in human pulmonary epithelial A549 cells. However, this enhanced IκBα synthesis did not cause repression of NF-κB DNA-binding activity. In addition, dexamethasone was still able to inhibit the expression of NF-κB target genes (cyclooxygenase-2, intercellular adhesion molecule-1) in the absence of protein synthesis. Furthermore, we show that the antihormone RU486 did not induce IκBα expression. However, RU486 was still able to induce, albeit less efficiently, both glucocorticoid- and progesterone receptor-mediated repression of endogenous NF-κB target gene expression in A549 cells and the breast cancer cell line T47D, respectively. Taken together, these results indicate that induced IκBα expression accounts for only part of the repression of NF-κB activity by glucocorticoids and progestins. In addition, protein-protein interactions between NF-κB and the glucocorticoid or progesterone receptor, resulting in repression of NF-κB activity, seem also to be involved. We therefore conclude that NF-κB activity is repressed via a dual mechanism involving both protein-protein interactions and induction of IκBα.