一种由核因子κB/RelA抑制转化生长因子-β/信号转导和转录激活因子信号的机制。
A mechanism of suppression of TGF-beta/SMAD signaling by NF-kappa B/RelA.
作者信息
Bitzer M, von Gersdorff G, Liang D, Dominguez-Rosales A, Beg A A, Rojkind M, Böttinger E P
机构信息
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461 USA.
出版信息
Genes Dev. 2000 Jan 15;14(2):187-97.
A number of pathogenic and proinflammatory stimuli, and the transforming growth factor-beta (TGF-beta) exert opposing activities in cellular and immune responses. Here we show that the RelA subunit of nuclear factor kappaB (NF-kappaB/RelA) is necessary for the inhibition of TGF-beta-induced phosphorylation, nuclear translocation, and DNA binding of SMAD signaling complexes by tumor necrosis factor-alpha (TNF-alpha). The antagonism is mediated through up-regulation of Smad7 synthesis and induction of stable associations between ligand-activated TGF-beta receptors and inhibitory Smad7. Down-regulation of endogenous Smad7 by expression of antisense mRNA releases TGF-beta/SMAD-induced transcriptional responses from suppression by cytokine-activated NF-kappaB/RelA. Following stimulation with bacterial lipopolysaccharide (LPS), or the proinflammatory cytokines TNF-alpha and interleukin-1beta (IL-1beta, NF-kappaB/RelA induces Smad7 synthesis through activation of Smad7 gene transcription. These results suggest a mechanism of suppression of TGF-beta/SMAD signaling by opposing stimuli mediated through the activation of inhibitory Smad7 by NF-kappaB/RelA.
许多致病和促炎刺激以及转化生长因子-β（TGF-β）在细胞和免疫反应中发挥相反的作用。在此我们表明，核因子κB（NF-κB/RelA）的RelA亚基对于肿瘤坏死因子-α（TNF-α）抑制TGF-β诱导的SMAD信号复合物的磷酸化、核转位及DNA结合是必需的。这种拮抗作用是通过上调Smad7的合成以及诱导配体激活的TGF-β受体与抑制性Smad7之间的稳定结合来介导的。通过反义mRNA的表达下调内源性Smad7可使TGF-β/SMAD诱导的转录反应从细胞因子激活的NF-κB/RelA的抑制中释放出来。在用细菌脂多糖（LPS）或促炎细胞因子TNF-α和白细胞介素-1β（IL-1β）刺激后，NF-κB/RelA通过激活Smad7基因转录来诱导Smad7的合成。这些结果提示了一种由NF-κB/RelA激活抑制性Smad7介导的相反刺激抑制TGF-β/SMAD信号传导的机制。
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