Cross-talk between nuclear factor-κB and the steroid hormone receptors:: Mechanisms of mutual antagonism
Cross-talk between nuclear factor-κB and the steroid hormone receptors:: Mechanisms of mutual antagonism
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DOI：
10.1210/mend.12.1.0044
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发表时间：
1998-01-01
影响因子：
--
通讯作者：
Cidlowski, JA
中科院分区：
文献类型：
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作者：
McKay, LI;Cidlowski, JA
核因子-kappaB(NF-kappa B)是一种可诱导的转录因子，可正向调节免疫前基因和炎症基因的表达，而糖皮质激素则是免疫和炎症反应的有力抑制因子。核因子-kappa B与糖皮质激素受体(GR)在物理上相互作用，从而抑制核因子-kappaB的反式激活。在瞬时共转染实验中，我们证明了NF-kappa B和GR之间存在剂量依赖的相互拮抗作用。对核因子-kappa B p50和p65亚基以及GR缺失突变体的功能分析表明，GR拮抗作用是针对核因子-kappa B异源二聚体p65亚基的，而GR的多个结构域是抑制p65介导的反式激活所必需的。尽管p65抑制了GR的反式激活，但它不能阻断反式抑制的GR同源下调功能。我们还证明，p65和GR之间的负相互作用不仅对GR具有选择性，而且还发生在核因子-kappaB与雄激素、孕激素B和雌激素受体之间。然而，尽管这些类固醇激素受体家族的每个成员都受到核因子-kappa B的抑制，但只有GR有效地抑制了p65的反式激活。此外，在使用嵌合雌激素-GR的共转染中，GR DNA结合域的存在不足以赋予p65-雌激素受体相互作用相互拮抗。通过I-kappa B从核因子-kappaB介导的抑制中拯救，证明了p65对每个类固醇受体的抑制的选择性。总之，这些数据表明，核因子-kappa B p65在物理上与多个类固醇激素受体相互作用，这种相互作用足以反式抑制每个类固醇激素受体。此外，细胞的核因子-kappa B状态有可能显著改变该细胞内的多个类固醇信号通路。
Nuclear factor kappa B (NF-kappa B) is an inducible transcription factor that positively regulates the expression of proimmune and proinflammatory genes, while glucocorticoids are potent suppressors of immune and inflammatory responses. NF-kappa B and the glucocorticoid receptor (GR) physically interact, resulting in repression of NF-kappa B transactivation. In transient cotransfection experiments, we demonstrate a dose-dependent, mutual antagonism between NF-kappa B and GR. Functional dissection of the NF-kappa B p50 and p65 subunits and deletion mutants of GR indicate that the GR antagonism is specific to the p65 subunit of NF-kappa B heterodimer, whereas multiple domains of GR are essential to repress p65-mediated transactivation. Despite its repression of GR transactivation, p65 failed to block the transrepressive GR homologous down-regulation function. We also demonstrate that negative interactions between p65 and GR are not selective for GR, but also occur between NF-kappa B and androgen, progesterone B, and estrogen receptors. However, although each of these members of the steroid hormone receptor family is repressed by NF-kappa B, only GR effectively inhibits p65 transactivation. Further, in cotransfections using a chimeric estrogen-GR, the presence of the GR DNA-binding domain is insufficient to confer mutual antagonism to the p65-estrogen receptor interaction. Selectivity of p65 repression for each steroid receptor is demonstrated by I kappa B rescue from NF-kappa B-mediated inhibition. Together these data suggest that NF-kappa B p65 physically interacts with multiple steroid hormone receptors, and this interaction is sufficient to transrepress each steroid receptor. Further, the NF-kappa B status of a cell has the potential to significantly alter multiple steroid signaling pathways within that cell.