Downregulation of OCTN2 by cytokines plays an important role in the progression of inflammatory bowel disease
Downregulation of OCTN2 by cytokines plays an important role in the progression of inflammatory bowel disease
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细胞因子下调 OCTN2 在炎症性肠病的进展中发挥重要作用
DOI：
10.1016/j.bcp.2020.114115
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发表时间：
2020
影响因子：
5.8
通讯作者：
Huidi Jiang
中科院分区：
文献类型：
--
作者：
Ping Li;Yuqing Wang;Jun Luo;Qingquan Zeng;Miaojuan Wang;Mengru Bai;Hui Hui;Jinhai Wang;Huidi Jiang
炎症性肠病（IBD）以胃肠道慢性复发性疾病为特征。OCTN2 （SLC22A5）及其层底肉碱（l-Car）在维持正常肠道功能中起着至关重要的作用。本研究的目的是描述OCTN2在IBD中的表达改变及其潜在机制。我们还研究了OCTN2对IBD进展的影响以及通过OCTN2调节改善IBD的可能性。我们的研究结果显示，IBD患者和小鼠炎症结肠组织中OCTN2表达水平和l- car含量下降，与IBD小鼠结肠炎症程度呈负相关。混合促炎因子TNF-α、IL-1β和IFNγ通过PPARγ/RXRα途径下调OCTN2的表达，随后降低了FHC细胞中el- car的含量。OCTN2沉默降低了结肠细胞的增殖率，而OCTN2过表达增加了增殖率。此外，PPARγ激动剂木犀草素增加OCTN2表达的能力导致结肠炎症反应的减轻。综上所述，IBD中OCTN2被促炎因子通过PPARγ/RXRα途径下调，从而降低了- car浓度，导致IBD恶化。PPARγ激动剂上调OCTN2可减轻结肠炎症。我们的研究结果表明，OCTN2可能作为IBD治疗的治疗靶点。
Inflammatory bowel diseases (IBD) are characterized by chronic relapsing disorders of the gastrointestinal tract. OCTN2 (SLC22A5) and its substratel-carnitine (l-Car) play crucial roles in maintaining normal intestinal function. An aim of this study was to delineate the expression alteration of OCTN2 in IBD and its underlying mechanism. We also investigated the impact of OCTN2 on IBD progression and the possibility of improving IBD through OCTN2 regulation. Our results showed decreased OCTN2 expression levels andl-Car content in inflamed colon tissues of IBD patients and mice, which negatively correlated with the degree of colonic inflammation in IBD mice. Mixed proinflammatory cytokines TNF-α, IL-1β and IFNγ downregulated the expression of OCTN2 and subsequently reduced thel-Car content through PPARγ/RXRα pathways in FHC cells. OCTN2 silencing reduced the proliferation rate of the colon cells, whereas OCTN2 overexpression increased the proliferation rate. Furthermore, the ability of PPARγ agonist, luteolin, to increase OCTN2 expression resulted in the alleviation of colonic inflammatory responses. In conclusion, OCTN2 was downregulated in IBD by proinflammatory cytokines via the PPARγ/RXRα pathways, which reducedl-Car concentration and subsequently induced IBD deterioration. Upregulation of OCTN2 by the PPARγ agonist alleviated colonic inflammation. Our findings suggest that, OCTN2 may serve as a therapeutic target for IBD therapy.