Up-regulation and Cytoprotective Role of Epithelial Multidrug Resistance-associated Protein 1 in Inflammatory Bowel Disease
Up-regulation and Cytoprotective Role of Epithelial Multidrug Resistance-associated Protein 1 in Inflammatory Bowel Disease
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DOI：
10.1074/jbc.m804374200
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发表时间：
2008-12-19
影响因子：
4.8
通讯作者：
Faber, Klaas Nico
中科院分区：
文献类型：
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作者：
Blokzijl, Hans;Van Steenpaal, Axel;Faber, Klaas Nico
MRP1(多药耐药相关蛋白1)因其在肿瘤细胞多药耐药中的作用而广为人知。此外，MRP1还与非恶性细胞的促炎和抗炎功能有关。MRP1是半胱氨酰白三烯C-4(LTC4)的高亲和力转运体，是炎症的脂质介质，从这一事实可以明显看出MRP1的促炎作用。然而，为什么MRp1的缺失会导致用葡聚糖-硫酸钠治疗的小鼠肠道上皮损伤增加，这一炎症性肠病(IBD)的模型仍未得到解释。我们发现，在炎症性肠病患者的炎性肠段，如克罗恩病和溃疡性结肠炎，MRP1的表达被诱导。肠上皮细胞基底膜MRP1表达增强。为了研究MRP1在保护上皮细胞免受炎症信号影响方面的可能作用，我们操纵了人上皮DLD-1细胞中MRP1的水平，并将这些细胞暴露于细胞因子和抗Fas。抑制MRP1(通过MK571或RNA干扰)导致细胞因子和抗Fas诱导的DLD-1细胞凋亡增加。在重组MRP1过表达后，观察到相反的作用，如保护DLD-1细胞免受细胞因子和抗Fas诱导的凋亡。当MRP1功能被阻断时，抑制LTC4的合成减少了抗Fas诱导的细胞凋亡，提示LTC4是上皮性MRP1在炎症过程中释放的促凋亡化合物。这些数据表明，MRP1保护肠上皮细胞免受炎症诱导的细胞凋亡，并在IBD患者炎症的肠上皮中提供MRP1的功能作用。
MRP1 (multidrug resistance-associated protein 1) is well known for its role in providing multidrug resistance to cancer cells. In addition, MRP1 has been associated with both pro- and anti-inflammatory functions in nonmalignant cells. The pro- inflammatory function is evident from the fact that MRP1 is a high affinity transporter for cysteinyl-leukotriene C-4 (LTC4), a lipid mediator of inflammation. It remains unexplained, however, why the absence of Mrp1 leads to increased intestinal epithelial damage in mice treated with dextran-sodium sulfate, a model for inflammatory bowel disease (IBD). We found that MRP1 expression is induced in the inflamed intestine of IBD patients, e. g. Crohn disease and ulcerative colitis. Increased MRP1 expression was detected at the basolateral membrane of intestinal epithelial cells. To study a putative role for MRP1 in protecting epithelial cells against inflammatory cues, we manipulated MRP1 levels in human epithelial DLD-1 cells and exposed these cells to cytokines and anti-Fas. Inhibition of MRP1 (by MK571 or RNA interference) resulted in increased cytokine- and anti-Fas-induced apoptosis of DLD-1 cells. Opposite effects, e. g. protection of DLD-1 cells against cytokine- and anti-Fas-induced apoptosis, were observed after recombinant MRP1 overexpression. Inhibition of LTC4 synthesis reduced anti-Fas-induced apoptosis when MRP1 function was blocked, suggesting that LTC4 is the pro- apoptotic compound exported by epithelial MRP1 during inflammation. These data show that MRP1 protects intestinal epithelial cells against inflammation-induced apoptotic cell death and provides a functional role for MRP1 in the inflamed intestinal epithelium of IBD patients.