I kappa B alpha-independent downregulation of NF-kappa B activity by glucocorticoid receptor

I kappa B alpha is an inhibitor protein that prevents nuclear transport and activation of the transcription factor NF-kappa B, In acute inflammation, NF-kappa B is activated and increases the expression of several pro-inflammatory cytokine and chemokine genes. Glucocorticoids counteract this process, It has been proposed that the glucocorticoid-dependent inhibition of NF-kappa B activity is mediated by increased synthesis 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 glucocorticoid receptor and steroidal ligands that hormone-induced I kappa B alpha synthesis and inhibition of NF-kappa B activity are separable biochemical 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 competent in enhancing I kappa B alpha synthesis do not repress NF-kappa B activity, These results demonstrate that increased synthesis of I kappa B alpha is neither required nor sufficient for the hormone-mediated downmodulation of NF-kappa B activity.