SLC26A3 (DRA) prevents TNF-alpha-induced barrier dysfunction and dextran sulfate sodium-induced acute colitis
SLC26A3 (DRA) prevents TNF-alpha-induced barrier dysfunction and dextran sulfate sodium-induced acute colitis
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SLC26A3 (DRA) 预防 TNF-α 诱导的屏障功能障碍和硫酸葡聚糖钠诱导的急性结肠炎
DOI：
10.1038/s41374-017-0005-4
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发表时间：
2018-04-01
影响因子：
5
通讯作者：
Yu, Qin
中科院分区：
文献类型：
--
作者：
Ding, Xiangming;Li, Dongxiao;Yu, Qin
SLC 26 A3编码Cl-/HCO 3（-）离子转运蛋白，其也被称为在腺瘤（腺瘤）中下调，并参与HCO 3-/粘液形成。在上皮屏障中的作用以前尚未建立。在这项研究中，我们研究了在体内和体外的结肠上皮屏障中的作用机制。免疫荧光（IF）和免疫共沉淀（co-IP）研究表明，在极化的Caco-2BBe细胞中，cytokine直接与紧密连接（TJ）蛋白结合，并影响TJ蛋白的表达。类似地，在肠上皮细胞中，Ep与ZO-1共定位。敲低或过度表达的tj导致改变蛋白质和上皮通透性。此外，TNF-α治疗通过激活NF-κ B并随后影响肠上皮屏障完整性来下调TNF-α。此外，过表达TNF-α通过稳定TJ蛋白部分逆转TNF-α诱导的损伤。在葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠中TNF-α的中和显示出改善的结果，并且TNF-α中和mAb的治疗效果部分地通过保留TNF-α表达来介导。这些数据表明，TNF-α可能是TNF-α的治疗靶点之一。此外，通过腺病毒载体递送的LPS通过促进DSS治疗的小鼠中TJ蛋白的恢复而显著防止结肠炎的恶化并改善上皮屏障功能。总之，ESTA在保护上皮屏障的作用，并可能是一个治疗目标，在肠道内稳态。
SLC26A3 encodes a Cl-/HCO3(-) ion transporter that is also known as downregulated in adenoma (DRA) and is involved in HCO3-/mucus formation. The role of DRA in the epithelial barrier has not been previously established. In this study, we investigated the in vivo and in vitro mechanisms of DRA in the colon epithelial barrier. Immunofluorescence (IF) and coimmunoprecipitation (co-IP) studies reveal that DRA binds directly to tight junction (TJ) proteins and affects the expression of TJ proteins in polarized Caco-2BBe cells. Similarly, DRA colocalizes with ZO-1 in the intestinal epithelium. Knockdown or overexpression of DRA leads to alterations in TJ proteins and epithelial permeability. In addition, TNF-alpha treatment downregulates DRA by activating NF-kappa B and subsequently affecting intestinal epithelial barrier integrity. Furthermore, overexpression of DRA partly reverses the TNF-alpha-induced damage by stabilizing TJ proteins. Neutralization of TNF-alpha in dextran sulfate sodium (DSS)-induced colitis mice demonstrates improved the outcomes, and the therapeutic effect of the TNF-alpha neutralizing mAb is mediated in part by the preservation of DRA expression. These data suggest that DRA may be one of the therapeutic targets of TNF-alpha. Moreover, DRA delivered by adenovirus vector significantly prevents the exacerbation of colitis and improves epithelial barrier function by promoting the recovery of TJ proteins in DSS-treated mice. In conclusion, DRA plays a role in protecting the epithelial barrier and may be a therapeutic target in gut homeostasis.