Involvement of a Stat3 binding site in inflammation-induced enteric apelin expression
Involvement of a Stat3 binding site in inflammation-induced enteric apelin expression
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DOI：
10.1152/ajpgi.90493.2008
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发表时间：
2008-11-01
影响因子：
4.5
通讯作者：
Greeley, George H., Jr.
中科院分区：
文献类型：
--
作者：
Han, Song;Wang, Guiyun;Greeley, George H., Jr.
Apelin是APJ受体的内源性配体；两者都在胃肠道表达。啮齿类动物的实验性结肠炎和人类的炎症性肠病与肠道apelin的产生增加有关。我们的目的是使用内毒素和致炎细胞因子(IL-6和干扰素-γ)处理的啮齿动物或肠道细胞来确定炎症诱导肠道apelin表达的信号机制。脂多糖、IL-6或干扰素-γ处理增加了啮齿动物肠道apelin的表达。药物阻断JAK/STAT信号通路或给予IL-6抗体可抑制肠内apelin表达的升高。瞬时转染实验表明，内毒素、IL-6或干扰素-γ通过刺激apelin启动子活性而增加apelin的表达，阻断Jak/Stat信号通路可抑制apelin启动子活性的升高。染色质免疫沉淀分析表明，IL-6诱导磷酸化的STAT3与apelin启动子中的STAT3位点结合，该位点的突变消除了内毒素诱导的apelin启动子活性的升高。总之，我们的发现表明，在肠道炎症过程中，磷酸化STAT3与apelin启动子的结合是促炎细胞因子诱导肠内apelin表达的最后一步。
Apelin is the endogenous ligand for the APJ receptor; both are expressed in the gastrointestinal tract. Experimental colitis in rodents and inflammatory bowel disease in humans are associated with increased intestinal apelin production. Our aim was to use LPS and proinflammatory cytokine-treated (IL-6 and IFN-gamma) rodents or enteric cells to identify signaling mechanisms underlying inflammation-induced enteric apelin expression. LPS, IL-6, or IFN-gamma treatment of rodents increased enteric apelin expression. Pharmacological blockade of Jak/Stat signaling or IL-6 antibody administration inhibited elevations in enteric apelin expression. Transient transfection experiments showed that LPS, IL-6, or IFN-gamma increased apelin expression by stimulation of apelin promoter activity, and blockade of Jak/Stat signaling abolished elevations in apelin promoter activity. A chromatin immunoprecipitation assay showed that IL-6 induced binding of phospho-Stat3 to a putative Stat3 site in the apelin promoter; mutation of this site abrogated the LPS-induced elevation in apelin promoter activity. Together, our findings indicate that binding of phospho-Stat3 to the apelin promoter is the final step underlying proinflammatory cytokine-induced enteric apelin expression during intestinal inflammation.