Inhibition of the transforming growth factor β (TGFβ) pathway by interleukin-1β is mediated through TGFβ-activated kinase 1 phosphorylation of SMAD3
Inhibition of the transforming growth factor β (TGFβ) pathway by interleukin-1β is mediated through TGFβ-activated kinase 1 phosphorylation of SMAD3
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DOI：
10.1091/mbc.e04-11-1033
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发表时间：
2005-08-01
影响因子：
3.3
通讯作者：
Eggen, BJL
中科院分区：
文献类型：
--
作者：
Benus, GFJD;Wierenga, ATJ;Eggen, BJL
转化生长因子13是调节多种生物过程的一大家族分泌因子的原型。在免疫系统中，TGF β是一种抗炎和免疫抑制分子，而细胞因子白细胞介素(IL)-1 β是炎症反应的重要介质，可诱导促炎基因和急性期蛋白。在这里，我们提供了IL-1 β和TGF β信号级联之间存在直接抑制相互作用的证据，该相互作用不依赖于IL-1 β诱导的SMAD7表达。IL-1 β及其下游介质TAK1抑制SMAD3介导的TGF β靶基因激活，而SMAD3核易位和响应TGF β的DNA结合不受影响。IL-1 β瞬时诱导TAK1与SMAD3的MAD同源2结构域之间的关联，导致SMAD3磷酸化。IL-1 β可以缓解TGF β对体外造血髓系集落形成的抑制作用。综上所述，我们的数据证明IL-1 β - tak1通路对smad3介导的TGF - β信号通路存在直接抑制作用，从而降低TGF - β靶基因的激活，恢复造血祖细胞的增殖。
Transforming growth factor 13 is the prototype of a large family of secreted factors that regulate multiple biological processes. In the immune system, TGF beta acts as an anti-inflammatory and immunosuppressive molecule, whereas the cytokine interleukin (IL)-1 beta is a crucial mediator of inflammatory responses and induces proinflammatory genes and acute phase proteins. Here, we present evidence for the existence of a direct inhibitory interaction between the IL-1 beta and TGF beta signaling cascades that is not dependent on IL-1 beta-induced SMAD7 expression. IL-1 beta and its downstream mediator TAK1 inhibit SMAD3-mediated TGF beta target gene activation, whereas SMAD3 nuclear translocation and DNA binding in response to TGF beta are not affected. IL-1 beta transiently induces association between TAK1 and the MAD homology 2 domain of SMAD3, resulting in SMAD3 phosphorylation. Furthermore, IL-1 beta alleviates the inhibitory effect of TGF beta on in vitro hematopoietic myeloid colony formation. In conclusion, our data provide evidence for the existence of a direct inhibitory effect of the IL-1 beta-TAK1 pathway on SMAD3-mediated TGF beta signaling, resulting in reduced TGF beta target gene activation and restored proliferation of hematopoietic progenitors.