人类 REG 家族基因在炎症性肠病中的表达及其分子机制。
Expression of human REG family genes in inflammatory bowel disease and their molecular mechanism.
机构信息
Department of Biochemistry, Nara Medical University, Kashihara, 634-8521, Japan.
Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan.
出版信息
Immunol Res. 2018 Dec;66(6):800-805. doi: 10.1007/s12026-019-9067-2.
The pathophysiology of inflammatory bowel disease (IBD) reflects a balance between mucosal injury and reparative mechanisms. Some regenerating gene (Reg) family members have been reported to be expressed in Crohn's disease (CD) and ulcerative colitis (UC) and to be involved as proliferative mucosal factors in IBD. However, expression of all the REG family genes in IBD is still unclear. Here, we analyzed expression of all the REG family genes (REGIα, REGIβ, REG III, HIP/PAP, and REG IV) in biopsy specimens of UC and CD by real-time RT-PCR. REG Iα, REG Iβ, and REG IV genes were overexpressed in CD samples. REG IV gene was also overexpressed in UC samples. We further analyzed the expression mechanisms of REG Iα, REG Iβ, and REG IV genes in LS-174T and HT-29 human colonic epithelial cells. The expression of REG Iα was significantly induced by IL-6 or IL-22, and REG Iβ was induced by IL-22. Deletion analyses revealed that three regions (- 220- 211, - 179- 156, and - 146- 130) in REG Iα and the region (- 274- 260) in REG Iβ promoter were responsible for the activation by IL-22/IL-6. The promoters contain consensus transcription factor binding sequences for MZF1, RTEF1/TEAD4, and STAT3 in REG Iα, and HLTF/FOXN2F in REG Iβ, respectively. The introduction of siRNA for MZF1, RTEF1/TEAD4, STAT3, and HLTF/FOXN2F abolished the transcription of REG Iα and REG Iβ. The gene activation mechanisms of REG Iα/REG Iβ may play a role in colon mucosal regeneration in IBD.
炎症性肠病（IBD）的病理生理学反映了黏膜损伤和修复机制之间的平衡。已经报道了一些再生基因（Reg）家族成员在克罗恩病（CD）和溃疡性结肠炎（UC）中表达，并作为 IBD 中的增殖性黏膜因子参与。然而，IBD 中所有 REG 家族基因的表达仍然不清楚。在这里，我们通过实时 RT-PCR 分析了 UC 和 CD 活检标本中所有 REG 家族基因（REGIα、REGIβ、REG III、HIP/PAP 和 REG IV）的表达。CD 样本中 REG Iα、REG Iβ 和 REG IV 基因过表达。我们进一步分析了 LS-174T 和 HT-29 人结肠上皮细胞中 REG Iα、REG Iβ 和 REG IV 基因的表达机制。IL-6 或 IL-22 显著诱导 REG Iα 的表达，而 IL-22 诱导 REG Iβ 的表达。缺失分析表明，REG Iα 中的三个区域（-220-211、-179-156 和-146-130）和 REG Iβ 启动子中的区域（-274-260）负责 IL-22/IL-6 的激活。启动子包含 REG Iα 中 MZF1、RTEF1/TEAD4 和 STAT3 的共识转录因子结合序列，以及 REG Iβ 中的 HLTF/FOXN2F。MZF1、RTEF1/TEAD4、STAT3 和 HLTF/FOXN2F 的 siRNA 引入消除了 REG Iα 和 REG Iβ 的转录。REG Iα/REG Iβ 的基因激活机制可能在 IBD 中发挥结肠黏膜再生的作用。
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