IκBα-independent downregulation of NF-κB activity by glucocorticoid receptor

IκBα is an inhibitor protein that prevents nuclear transport. and activation of the transcription factor NF-κB. In, acute inflammation, NF-κB 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-κB activity is mediated by increased synthesis of IκBα which should then sequester NF-κB in an inactive cytoplasmic form. Here, we show by the use of a mutant glucocorticoid receptor and steroidal ligands that hormone induced IκBα synthesis and inhibition of NF-κB activity are separable biochemical processes. A dimerizationd-defective glucocorticoid receptor mutant that does not enhance the IκBα level is still able to repress NF-κB activity. Conversely, glucocorticoid analogues competent in enhancing IκBα synthesis do not repress NF-κB activity. These results demonstrate that increased synthesis of IκBα is neither required nor sufficient for the hormone-mediated downmodulation of NF-κB activity.