I-KAPPA-B-ALPHA-INDEPENDENT DOWN-REGULATION OF NF-KAPPA-B ACTIVITY BYGLUCOCORTICOID RECEPTOR

I kappa B alpha is an inhibitor protein that prevents nuclear transpor t and activation of the transcription factor NF-kappa B, In acute infl ammation, NF-kappa B is activated and increases the expression of seve ral pro-inflammatory cytokine and chemokine genes. Glucocorticoids cou nteract this process, It has been proposed that the glucocorticoid-dep endent inhibition of NF-kappa B activity is mediated by increased synt hesis of I kappa B alpha which should then sequester NF-kappa B In an inactive cytoplasmic form, Here, we show by the use of a mutant glucoc orticoid receptor and steroidal ligands that hormone-induced I kappa B alpha synthesis and inhibition of NF-kappa B activity are separable b iochemical processes, A dimerization-defective glucocorticoid receptor mutant that does not enhance the I kappa B alpha level is still able to repress NF-kappa B activity, Conversely, glucocorticoid analogues c ompetent in enhancing I kappa B alpha synthesis do not repress NF-kapp a B activity, These results demonstrate that increased synthesis of I kappa B alpha is neither required nor sufficient for the hormone-media ted downmodulation of NF-kappa B activity.