Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease
Aberrant intestinal expression and allelic variants of mucin genes associated with inflammatory bowel disease
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DOI：
10.1007/s00109-006-0100-2
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发表时间：
2006-12-01
影响因子：
4.7
通讯作者：
Schmitz, Gerd
中科院分区：
文献类型：
--
作者：
Moehle, Christoph;Ackermann, Nikolaus;Schmitz, Gerd
肠黏膜完整性的丧失是炎症性肠病发病的重要因素（1131）。本研究的目的是表征该疾病中肠上皮屏障功能相关基因的表达变化和等位基因变异。因此，对溃疡性结肠炎（UC）和克罗恩病（CD）患者以及非ibd先证者的未受影响区域的回肠和结肠粘膜活检进行Affymetrix dna微阵列分析。实时逆转录聚合酶链反应用于较大IBD样本量的验证。在疾病组和组织中发现了几个粘蛋白基因的mRNA表达紊乱。结肠MUC2在CD和UC中显著下调，MUC12在CD和UC中显著下调。在广泛的人体组织面板中，所有失调的粘蛋白的表达分析显示显性上皮组织特异性转录。对这些粘蛋白调控区域的硅分析表明，核因子κ B （NF κ B）结合位点在每个启动子中。此外，NF kappa B在粘蛋白启动子和特定转录因子组合（复合模块）的组成部分中过度表达。在腺癌细胞系LS174T的体内刺激实验中，肿瘤坏死因子-a和转化生长因子- β可诱导mucin的表达，并可被NF κ B信号抑制剂阻断。等位基因鉴别筛查结果显示，MUC2-V116M多态性与CD、MUC4-A585S （P=0.025）、MUC13-R502S （P=0.0003）与UC的相关性具有统计学意义。这些数据表明，粘蛋白基因的表达紊乱以及与NF κ B通路的连接可能会影响肠道的完整性，从而促进IBD的病理生理。
Loss of intestinal mucosa integrity is an important factor in the pathogenesis of inflammatory bowel disease (1131)). The aim of this study was to characterize expression changes and allelic variants of genes related to intestinal epithelia] barrier function in this disease. Therefore, ileal and colonic mucosal biopsies from nonaffected regions of patients with ulcerative colitis (UC) and Crohn's disease (CD), as well as non-IBD probands, were subjected to Affymetrix DNA-microarray analysis. Real-time reverse transcription polymerase chain reaction was used for verification in larger IBD sample numbers. Disturbed mRNA expression was identified for several mucin genes in both disease groups and tissues. A significant down-regulation in the colon was obtained for MUC2 in CD and MUC12 in CD and UC. Expression analysis of all dysregulated mucins in a broad human tissue panel revealed dominant epithelial tissue-specific transcription. In silico analysis of the regulatory regions of these mucins indicated nuclear factor kappa B (NF kappa B) binding sites in each promoter. Furthermore, NF kappa B was overrepresented in mucin promoters and a component of a specific combination of transcription factors (composite module). In vivo stimulation experiments in the adenocarcinoma cell line LS174T showed inducible mucin expression by the cytokines tumor necrosis factor-a and transforming growth factor-beta, which could be blocked by NF kappa B signaling inhibitors. Allelic discrimination screening obtained statistically significant associations for the MUC2-V116M (P=0.003) polymorphism with CD and for MUC4-A585S (P=0.025), as well as MUC13-R502S (P=0.0003) with UC. These data suggest that the disturbed expression of mucin genes and the connection to the NF kappa B pathway may influence the integrity of the intestine and therefore contribute to the pathophysiology of IBD.