Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways
Regulation of IL-1β-induced NF-κB by hydroxylases links key hypoxic and inflammatory signaling pathways
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DOI：
10.1073/pnas.1309718110
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发表时间：
2013-11-12
影响因子：
11.1
通讯作者：
Taylor, Cormac T.
中科院分区：
文献类型：
--
作者：
Scholz, Carsten C.;Cavadas, Miguel A. S.;Taylor, Cormac T.
缺氧是慢性炎症组织的一个显著特征。氧感受羟基酶通过调节低氧诱导因子(HIF)和核因子-kappaB(NF-kappa B)来调控转录对低氧的适应，这两种因子都可以调节炎症反应。此外，在多种动物模型中，药理羟化酶抑制剂可减轻炎症。然而，将羟基酶活性与炎症信号联系起来的潜在机制(S)仍不清楚。IL-1β是一种主要的促炎细胞因子，调节核因子-kappaB，与多种炎症病理有关。我们证明，在肿瘤坏死因子受体相关因子6复合体的水平(或下游)，Pro羟基酶1和抑制HIF羟基酶异构体的因子组合可以调节IL-1β诱导的核因子-kappaB。IL-1β信号通路远端的多个蛋白质被羟化，并与Pro-羟基酶1或抑制HIF的因子形成复合体。因此，我们假设羟基酶调节IL-1β信号和随后的炎症基因表达。此外，羟基酶抑制是抑制IL-1β依赖的炎症信号的一种独特方法。
Hypoxia is a prominent feature of chronically inflamed tissues. Oxygen-sensing hydroxylases control transcriptional adaptation to hypoxia through the regulation of hypoxia-inducible factor (HIF) and nuclear factor kappa B (NF-kappa B), both of which can regulate the inflammatory response. Furthermore, pharmacologic hydroxylase inhibitors reduce inflammation in multiple animal models. However, the underlying mechanism(s) linking hydroxylase activity to inflammatory signaling remains unclear. IL-1 beta, a major proinflammatory cytokine that regulates NF-kappa B, is associated with multiple inflammatory pathologies. We demonstrate that a combination of prolyl hydroxylase 1 and factor inhibiting HIF hydroxylase isoforms regulates IL-1 beta-induced NF-kappa B at the level of (or downstream of) the tumor necrosis factor receptor-associated factor 6 complex. Multiple proteins of the distal IL-1 beta-signaling pathway are subject to hydroxylation and form complexes with either prolyl hydroxylase 1 or factor inhibiting HIF. Thus, we hypothesize that hydroxylases regulate IL-1 beta signaling and subsequent inflammatory gene expression. Furthermore, hydroxylase inhibition represents a unique approach to the inhibition of IL-1 beta-dependent inflammatory signaling.