Endotoxemia Induces IκBβ/NF-κB-Dependent Endothelin-1 Expression in Hepatic Macrophages.
Endotoxemia Induces IκBβ/NF-κB-Dependent Endothelin-1 Expression in Hepatic Macrophages.
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DOI：
10.4049/jimmunol.1501017
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发表时间：
2015-10-15
期刊：
影响因子：
--
通讯作者：
Wright CJ
中科院分区：
文献类型：
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作者：
McKenna S;Gossling M;Bugarini A;Hill E;Anderson AL;Rancourt RC;Balasubramaniyan N;El Kasmi KC;Wright CJ
血管活性蛋白 ET-1 的血清浓度升高发生在全身炎症反应综合征的情况下，并导致远端器官灌注不足和肺动脉高压。因此，了解全身炎症应激诱导的 ET-1 表达的细胞来源和转录调控可能会揭示治疗靶点。使用 LPS 诱导的败血性休克的小鼠模型，我们证明肝巨噬细胞是循环 ET-1 升高的主要来源，而不是之前提出的内皮细胞。使用药理学抑制剂、ET-1启动子荧光素酶测定，并通过沉默和过度表达 NFκB 抑制蛋白 IκB 表达，我们证明 LPS 诱导的 ET-1 表达是通过 NFκB 依赖性途径发生的。最后，评估了cRel/p65抑制蛋白IκBβ的具体作用。虽然细胞质 IκBβ 抑制含有 NFκB 二聚体的 cRel 的活性，但细胞核 IκBβ 稳定 NFκB/DNA 结合并增强基因表达。使用靶向药物疗法特异性阻止 IκBβ/NFκB 信号传导，以及通过基因改造过度表达 IκBβ 的小鼠，我们证明核 IκBβ 对于驱动 LPS 诱导的 ET-1 表达是必要且充分的。总之，这些结果在机制上将 IκBβ/NFκB 介导的先天免疫反应与 ET-1 表达联系起来，并可能揭示革兰氏阴性感染性休克患者的治疗靶点。
Elevated serum concentrations of the vasoactive protein ET-1 occur in the setting of systemic inflammatory response syndrome and contribute to distal organ hypoperfusion and pulmonary hypertension. Thus, understanding the cellular source and transcriptional regulation of systemic inflammatory stress-induced ET-1 expression may reveal therapeutic targets. Using a murine model of LPS-induced septic shock, we demonstrate that the hepatic macrophage is the primary source of elevated circulating ET-1, rather than the endothelium as previously proposed. Using pharmacologic inhibitors, ET-1 promoter luciferase assays, and by silencing and overexpressing NFκB inhibitory protein IκB expression, we demonstrate that LPS-induced ET-1 expression occurs via an NFκB dependent pathway. Finally, the specific role of the cRel/p65 inhibitory protein IκBβ was evaluated. Although cytoplasmic IκBβ inhibits activity of cRel containing NFκB dimers, nuclear IκBβ stabilizes NFκB/DNA binding and enhances gene expression. Using targeted pharmacologic therapies to specifically prevent IκBβ/NFκB signaling, as well as mice genetically modified to overexpress IκBβ, we show that nuclear IκBβ is both necessary and sufficient to drive LPS-induced ET-1 expression. Together, these results mechanistically link the innate immune response mediated by IκBβ/NFκB to ET-1 expression and potentially reveals therapeutic targets for patients with gram-negative septic shock.