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. 1997 Aug 1;16(15):4698–4707. doi: 10.1093/emboj/16.15.4698

I kappaB alpha-independent downregulation of NF-kappaB activity by glucocorticoid receptor.

S Heck 1, K Bender 1, M Kullmann 1, M Göttlicher 1, P Herrlich 1, A C Cato 1
PMCID: PMC1170096  PMID: 9303314

Abstract

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

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Selected References

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