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炎症过程的扩增环是由 P2X7R 激活诱导的,这种激活发生在响应中性粒细胞跨上皮迁移的肠道上皮细胞中。

Amplification loop of the inflammatory process is induced by P2X7R activation in intestinal epithelial cells in response to neutrophil transepithelial migration.

机构信息

Institut National de la Santé et de la Recherche Médicale (INSERM) ERI-21/EA 4319, 06107 Nice, Cedex 01, France.

出版信息

Am J Physiol Gastrointest Liver Physiol. 2010 Jul;299(1):G32-42. doi: 10.1152/ajpgi.00282.2009. Epub 2010 Feb 25.

Abstract

Inflammatory bowel diseases (IBD) are characterized during their active phase by polymorphonuclear leukocyte (PMNL) transepithelial migration. The efflux of PMNL into the mucosa is associated with the production of proinflammatory cytokines and the release of ATP from damaged and necrotic cells. The expression and function of purinergic P2X(7) receptor (P2X(7)R) in intestinal epithelial cells (IEC) and its potential role in the "cross talk" between IEC and PMNL have not been explored. The aims of the present study were 1) to examine P2X(7)R expression in IEC (T84 cells) and in human intestinal biopsies; 2) to detect any changes in P2X(7)R expression in T84 cells during PMNL transepithelial migration, and during the active and quiescent phases of IBD; and 3) to test whether P2X(7)R stimulation in T84 monolayers can induce caspase-1 activation and IL-1beta release by IEC. We found that a functional ATP-sensitive P2X(7)R is constitutively expressed at the apical surface of IEC T84 cells. PMNL transmigration regulates dynamically P2X(7)R expression and alters its distribution from the apical to basolateral surface of IEC during the early phase of PMNL transepithelial migration in vitro. P2X(7)R expression was weak in intestinal biopsies obtained during the active phase of IBD. We show that activation of epithelial P2X(7)R is mandatory for PMNL-induced caspase-1 activation and IL-1beta release by IEC. Overall, these changes in P2X(7)R function may serve to tailor the intensity of the inflammatory response and to prevent IL-1beta overproduction and inflammatory disease.

摘要

炎症性肠病(IBD)在其活动期的特征是多形核白细胞(PMN)穿过上皮细胞迁移。PMN 渗出到黏膜与促炎细胞因子的产生以及受损和坏死细胞释放 ATP 有关。肠上皮细胞(IEC)中嘌呤能 P2X(7)受体(P2X(7)R)的表达和功能及其在 IEC 和 PMNL 之间“串扰”中的潜在作用尚未被探索。本研究的目的是 1)检测 P2X(7)R 在 IEC(T84 细胞)和人肠活检中的表达;2)检测 PMNL 穿过上皮细胞迁移期间以及 IBD 活动期和静止期 T84 细胞中 P2X(7)R 表达的变化;3)检测 T84 单层细胞中 P2X(7)R 刺激是否可以诱导 IEC 中半胱天冬酶-1 的激活和 IL-1β的释放。我们发现功能性 ATP 敏感的 P2X(7)R 在 IEC T84 细胞的顶端表面持续表达。PMN 迁移动态调节 P2X(7)R 的表达,并在体外 PMNL 穿过上皮细胞迁移的早期改变其从顶端到基底外侧的分布。在 IBD 活动期获得的肠活检中 P2X(7)R 的表达较弱。我们表明,上皮细胞 P2X(7)R 的激活对于 PMNL 诱导的 IEC 中半胱天冬酶-1 的激活和 IL-1β的释放是必需的。总的来说,P2X(7)R 功能的这些变化可能有助于调整炎症反应的强度,并防止 IL-1β的过度产生和炎症性疾病。

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