IL-17A Synergistically Enhances Bile Acid-Induced Inflammation during Obstructive Cholestasis
IL-17A Synergistically Enhances Bile Acid-Induced Inflammation during Obstructive Cholestasis
复制标题
DOI：
10.1016/j.ajpath.2013.07.019
复制
发表时间：
2013-11-01
影响因子：
6
通讯作者：
Copple, Bryan L.
中科院分区：
文献类型：
--
作者：
O'Brien, Kate M.;Allen, Katryn M.;Copple, Bryan L.
在阻塞性胆汁淤积期间，胆汁酸浓度增加会激活肝细胞中的 ERK1/2，从而上调早期生长反应因子 1，这是促炎细胞因子的关键调节因子，如巨噬细胞炎症蛋白 2 (MIP-2)，进而加剧胆汁淤积性肝损伤。最近的研究表明，IL-17A 在阻塞性胆汁淤积期间导致肝脏炎症，这表明胆汁酸和 IL-17A 可能相互作用来调节肝脏炎症反应。我们用 IL-17A 中和抗体或对照 IgG 处理小鼠，并对它们进行胆管结扎。 IL-17A 的中和可防止促炎细胞因子的上调、肝脏中性粒细胞积聚和肝损伤，表明 IL-17A 在胆汁淤积期间的中性粒细胞炎症中发挥重要作用。用牛磺胆酸 (TCA) 处理原代小鼠肝细胞可增加 MIP-2 的表达。与 IL-17A 共同治疗可协同增强 TCA 对 MIP-2 的上调。与 MIP-2 相比，IL-17A 不影响 TCA 对 Egr-1 的上调，表明 IL-17A 不影响胆汁酸诱导的早期生长反应因子 1 上游信号通路的激活。此外，胆汁酸增加 IL-23 的表达，IL-23 是体外和体内肝细胞中 IL-17A 产生的关键调节因子。总的来说，这些数据表明胆汁酸是 IL-23/IL-17A 轴的新触发因素，并表明 IL-17A 通过协同增强胆汁酸诱导的肝细胞产生促炎细胞因子，从而促进胆汁淤积期间的肝脏炎症。
During obstructive cholestasis, increased concentrations of bile acids activate ERK1/2 in hepatocytes, which up-regulates early growth response factor 1, a key regulator of proinflammatory cytokines, such as macrophage inflammatory protein 2 (MIP-2), which, in turn, exacerbates cholestatic liver injury. Recent studies have indicated that IL-17A contributes to hepatic inflammation during obstructive cholestasis, suggesting that bile acids and IL-17A may interact to regulate hepatic inflammatory responses. We treated mice with an IL-17A neutralizing antibody or control IgG and subjected them to bile duct ligation. Neutralization of IL-17A prevented up-regulation of proinflammatory cytokines, hepatic neutrophil accumulation, and liver injury, indicating an important role for IL-17A in neutrophilic inflammation during cholestasis. Treatment of primary mouse hepatocytes with taurocholic acid (TCA) increased the expression of MIP-2. Co-treatment with IL-17A synergistically enhanced up-regulation of MIP-2 by TCA. In contrast to MIP-2, IL-17A did not affect up-regulation of Egr-1 by TCA, indicating that IL-17A does not affect bile acid-induced activation of signaling pathways upstream of early growth response factor 1. In addition, bile acids increased expression of IL-23, a key regulator of IL-17A production in hepatocytes in vitro and in vivo. Collectively, these data identify bile acids as novel triggers of the IL-23/IL-17A axis and suggest that IL-17A promotes hepatic inflammation during cholestasis by synergistically enhancing bile acid-induced production of proinflammatory cytokines by hepatocytes.