ROLE OF TRANSCRIPTIONAL ACTIVATION OF I-KAPPA-B-ALPHA IN MEDIATION OFIMMUNOSUPPRESSION BY GLUCOCORTICOIDS

Glucocorticoids are potent immunosuppressive drugs, but their mechanis m is poorly understood. Nuclear factor kappa B (NF-kappa B), a regulat or of immune system and inflammation genes, may be a target for glucoc orticoid-mediated immunosuppression. The activation of NF-kappa B invo lves the targeted degradation of its cytoplasmic inhibitor, I kappa B alpha, and the translocation of NF-kappa B to the nucleus. Here it is shown that the synthetic glucocorticoid dexamethasone induces the tran scription of the I kappa B alpha gene, which results in an increased r ate of I kappa B alpha protein synthesis. Stimulation by tumor necrosi s factor causes the release of NF-kappa B from I kappa B alpha. Howeve r, in the presence of dexamethasone this newly released NF-kappa B qui ckly reassociates with newly synthesized I kappa B alpha, thus markedl y reducing the amount of NF-kappa B that translocates to the nucleus. This decrease in nuclear NF-kappa B is predicted to markedly decrease cytokine secretion and thus effectively block the activation of the im mune system.