A DUAL MECHANISM MEDIATES REPRESSION OF NF-KAPPA-B ACTIVITY BY GLUCOCORTICOIDS

Repression of nuclear factor (NF)-kappa B-dependent gene expression is one of the key characteristics by which glucocorticoids exert their a ntiinflammatory and immunosuppressive effects. In vitro studies have s hown protein-protein interactions between NF-kappa B and the glucocort icoid receptor, possibly explaining their mutual repression of transcr iptional activity. Furthermore, glucocorticoid-induced transcription o f I kappa B alpha was presented as a mechanism in mediation of immunos uppression by glucocorticoids. At present, the relative contribution o f each mechanism has not been investigated, We show that dexamethasone induced I kappa B alpha gene transcription in human pulmonary epithel ial A549 cells, However, this enhanced I kappa B alpha synthesis did n ot cause repression of NF-kappa B DNA-binding activity. In addition, d examethasone was still able to inhibit the expression of NF-kappa B ta rget genes (cyclooxygenase-2, intercellular adhesion molecule-1) in th e absence of protein synthesis. Furthermore, we show that the antihorm one RU486 did not induce I kappa B alpha expression, However, RU486 wa s still able to induce, albeit less efficiently, both glucocorticoid-a nd progesterone receptor-mediated repression of endogenous NF-kappa B target gene expression in A549 cells and the breast cancer cell line T 47D, respectively. Taken together, these results indicate that induced I kappa B alpha expression accounts for only part of the repression o f 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 activ ity, seem also to be involved. We therefore conclude that NF-kappa B a ctivity is repressed via a dual mechanism involving both protein-prote in interactions and induction of I kappa B alpha.