Tumor necrosis factor-α acts reciprocally with solute carrier family 26, member 3, (downregulated-in-adenoma) and reduces its expression, leading to intestinal inflammation.
Tumor necrosis factor-α acts reciprocally with solute carrier family 26, member 3, (downregulated-in-adenoma) and reduces its expression, leading to intestinal inflammation.
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肿瘤坏死因子-α 与溶质载体家族 26、成员 3（在腺瘤中下调）相互作用并减少其表达，导致肠道炎症。
DOI：
10.3892/ijmm.2017.3347
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发表时间：
2018-03
影响因子：
5.4
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Ding X;Li D;Li M;Tian D;Yu H;Yu Q
溶质载体家族26，成员3（Slc 26 a3），也称为腺瘤中下调的（downregulated-in-adenoma，DLc），是阴离子转运蛋白Slc 26家族的成员，并且在先天性氯化物腹泻中突变。我们先前的研究表明，结肠炎缺乏与结肠HCO 3 −分泌严重减少、结肠液体吸收丧失、缺乏牢固粘附的粘液层以及结肠粘膜对葡聚糖硫酸钠（DSS）损伤的抵抗力严重降低有关。然而，触发肠道炎症因子的介质对结肠炎的直接影响尚未得到充分研究。肿瘤坏死因子（TNF）-α是炎症性肠病（IBD）（包括溃疡性结肠炎（UC）和克罗恩病）中肠道炎症的中心介质。然而，据我们所知，TNF-α是否与炎症因子共同作用，导致IBD肠道炎症的发展尚未报道。本研究发现，在活动性UC患者和DSS诱导的结肠炎小鼠中，TNF-α的表达水平降低，外周血血清中TNF-α的表达水平较高。此外，TNF-α可能以剂量依赖性方式影响人结肠Caco 2BBE细胞（包括过表达TNF-α的Caco 2BBE细胞）中TNF-α的表达水平。此外，在Caco 2BBE细胞中敲低TNF-α导致更高水平的TNF-α表达和在培养基中显著减少的TNF-α分泌。此外，与对照细胞相比，Caco 2BBE细胞中TNF-α的敲低导致培养基中TNF-α的分泌增加，这可以通过过表达TNF-α来逆转。总体而言，这些结果表明TNF-α可能与肠道炎症共同作用，导致肠道炎症的发展。基于TNF-α在IBD中的关键地位，假设TNF-α作为重要靶点具有对抗结肠炎的治疗潜力。
Solute carrier family 26, member 3 (Slc26a3), also termed downregulated-in-adenoma (DRA) is a member of the Slc26 family of anion transporters and is mutated in congenital chloride diarrhea. Our previous study demonstrated that DRA deficiency is associated with severely reduced colonic HCO3− secretion, a loss of colonic fluid absorption, a lack of a firmly adherent mucus layer and a severely reduced colonic mucosal resistance to dextran sodium sulfate (DSS) damage. However, the direct effect of mediators that trigger intestinal inflammatory factors on DRA has not been fully investigated. Tumor necrosis factor (TNF)-α is a central mediator of intestinal inflammation in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease. However, to the best of our knowledge, whether TNF-α acts reciprocally with DRA leading to the development of gut inflammation in IBD has not been reported. The present study identified that the expression level of DRA was reduced in active UC patients and DSS-induced colitis mice with high expression levels of TNF-α identified in the peripheral blood serum. In addition, TNF-α may affect the expression level of DRA in human colonic Caco2BBE cells in a dose-dependent manner, including in DRA overexpressed Caco2BBE cells. Furthermore, knockdown of TNF-α in Caco2BBE cells led to a higher expression level of DRA and a markedly reduced secretion of TNF-α in the culture media. In addition, knockdown of DRA in Caco2BBE cells led to a higher secretion of TNF-α in the culture media compared with the control cells, which could be reversed by overexpression of DRA. Overall, these results indicate that TNF-α may act reciprocally with DRA, leading to the development of intestinal inflammation. Based on the pivotal position of TNF-α in IBD, DRA is hypothesized to have therapeutic potential against colitis serving as an important target.
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