Heck S, Bender K, Kullmann M, Göttlicher M, Herrlich P, Cato A C
Forschungszentrum Karlsruhe, Institute of Genetics, Germany.
EMBO J. 1997 Aug 1;16(15):4698-707. doi: 10.1093/emboj/16.15.4698.
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.
IκBα是一种抑制蛋白，可阻止转录因子NF-κB的核转运及激活。在急性炎症中，NF-κB被激活并增加多种促炎细胞因子和趋化因子基因的表达。糖皮质激素可对抗这一过程。有人提出，糖皮质激素依赖性抑制NF-κB活性是由IκBα合成增加介导的，随后IκBα应以无活性的细胞质形式隔离NF-κB。在此，我们通过使用突变糖皮质激素受体和甾体配体表明，激素诱导的IκBα合成和NF-κB活性抑制是可分离的生化过程。一种不增强IκBα水平的二聚化缺陷型糖皮质激素受体突变体仍能抑制NF-κB活性。相反，能够增强IκBα合成的糖皮质激素类似物并不能抑制NF-κB活性。这些结果表明，IκBα合成增加对于激素介导的NF-κB活性下调既非必需也不充分。
