Ikappa Balpha -independent downregulation of NF-kappa B activity by glucocorticoid receptor

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Abstract
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 dimerization‐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.