Smad6 negatively regulates interleukin 1-receptor Toll-like receptor signaling through direct interaction with the adaptor Pellino-1
Smad6 negatively regulates interleukin 1-receptor Toll-like receptor signaling through direct interaction with the adaptor Pellino-1
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DOI：
10.1038/ni1383
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发表时间：
2006-10-01
影响因子：
30.5
通讯作者：
Park, Seok Hee
中科院分区：
文献类型：
--
作者：
Choi, Kyung-Chul;Lee, Youn Sook;Park, Seok Hee
转化生长因子-β1(TGF-β1)是一种强大的细胞因子，具有多种作用，包括抗炎活性。在这里，我们发现信号蛋白Smad6与哺乳动物白介素1受体(IL-1R)相关激酶1(IRAK1)的接头蛋白Pellino-1结合，从而促进了转化生长因子-β介导的抗炎作用。Smad6-Pellino-1相互作用可阻断IL-1β刺激后形成的IRAK1、Pellino-1和适配蛋白TRAF6的复合体介导的信号转导。阻断IRAK1-Pellino-1-TRAF6信号通路可阻止抑制物I kappa Bα的降解和随后转录因子NF-kappa B的核转位，从而阻止促炎基因的表达。通过RNA干扰抑制内源性Smad6的表达可降低由转化生长因子-β1或转化生长因子-β家族成员骨形态发生蛋白-4介导的抗炎活性。因此，Smad6是转化生长因子-β-骨形态发生蛋白途径的关键介质，该途径介导抗炎活性，并负向调节IL-1R-Toll样受体信号。
Transforming growth factor-beta 1 (TGF-beta 1) is a potent cytokine with pleiotropic effects, including anti-inflammatory activity. Here we show that the signaling protein Smad6 bound to Pellino-1, an adaptor protein of mammalian interleukin 1 receptor (IL-1R) associated kinase 1 ( IRAK1), and thereby promoted TGF-beta-mediated anti-inflammatory effects. Smad6-Pellino-1 interaction abrogated signaling mediated by a complex of IRAK1, Pellino-1 and adaptor protein TRAF6 that formed after stimulation by IL-1 beta treatment. Blockade of IRAK1-Pellino-1-TRAF6 signaling prevented degradation of the inhibitor I kappa B alpha and subsequent nuclear translocation of transcription factor NF-kappa B and thus expression of proinflammatory genes. 'Knockdown' of endogenous Smad6 expression by RNA interference reduced anti-inflammatory activity mediated by TGF-beta 1 or the TGF-beta family member BMP-4. Thus Smad6 is a critical mediator of the TGF-beta-BMP pathway that mediates anti-inflammatory activity and negatively regulates IL-1R-Toll-like receptor signals.