I kappaB alpha-independent downregulation of NF-kappaB activity by glucocorticoid receptor.
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.
Heck
S
S
Forschungszentrum Karlsruhe, Institute of Genetics, Germany.
Bender
K
K
Kullmann
M
M
Göttlicher
M
M
Herrlich
P
P
Cato
A C
AC
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology; D019281:Dimerization; D015536:Down-Regulation; D004958:Estradiol / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D017931:DNA Primers; D004268:DNA-Binding Proteins; D005938:Glucocorticoids; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; D011965:Receptors, Glucocorticoid; D013196:Dihydrotestosterone; D000072000:NF-KappaB Inhibitor alpha; D004958:Estradiol