Comparative proteomic studies on the pathogenesis of human ulcerative colitis
Comparative proteomic studies on the pathogenesis of human ulcerative colitis
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DOI：
10.1002/pmic.200500541
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发表时间：
2006-10-01
期刊：
影响因子：
3.4
通讯作者：
Lee, Ying-Shiung
中科院分区：
文献类型：
--
作者：
Hsieh, Sen-Yung;Shih, Tsung-Chieh;Lee, Ying-Shiung
溃疡性结肠炎(UC)是一种主要影响结肠粘膜的慢性炎症性疾病。其病因和发病机制尚不清楚。我们使用2-DE和MS来鉴定UC活动期、非活动期、非特异性结肠炎和正常结肠黏膜之间的差异表达蛋白质。共鉴定出13个下调蛋白和6个上调蛋白。在下调表达的蛋白质中，8个(热休克蛋白90(HSPA9B)、热休克蛋白60(HSPD 1)、H+转运蛋白ATP5B、抑制素(PHB)、线粒体苹果酸脱氢酶(MDH2)、电压依赖阴离子选择通道蛋白1(VDAC1)、硫氧还蛋白过氧化物酶(PRDX1)和硫醇特异性抗氧化剂(PRDX2))是线粒体蛋白，3个(ATP5B、MDH2、三糖磷酸异构酶)参与能量产生，3个(PRX1、PRDX2、SELENBP1)是细胞抗氧化剂，6个(HSPD1、HSPA9B、PRDX1、DPRX2、PHB、VDAC1)是应激反应蛋白。透射电子显微镜显示线粒体超微结构的病理改变，甚至在结肠粘膜中的整体结肠细胞改变之前。PHB是一种重要的线粒体组成蛋白，在UC患者的疾病活动期和非活动期结肠粘膜中均呈低表达，提示UC发生发展过程中线粒体发生了早期变化。相反，在UC患者的结肠粘膜中发现了NFAT的异常激活和潜在免疫原蛋白(肿瘤排斥抗原1和脊髓灰质炎病毒受体相关蛋白1)的异位表达。我们的发现提示结肠细胞线粒体功能障碍和黏膜免疫调节紊乱在UC的发病机制中的意义，并为新的治疗方法的开发提供了潜在的靶点。
Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the colon mucosa. Its etiology and pathogenesis remain unclear. We used 2-DE and MS to identify differentially expressed proteins among the UC active, UC inactive, nonspecific colitis, and normal colon mucosa. Thirteen down-regulated and six up-regulated proteins were identified. Of the down-expressed proteins, eight (heat-shock protein 90 (HSPA9B), heat-shock protein 60 (HSPD1), H+-transporting two-sector ATPase (ATP5B), prohibitin (PHB), mitochondrial malate dehydrogenase (MDH2), voltage-dependent anion-selective channel protein 1 (VDAC1), thioredoxin peroxidase (PRDX1), and thiol-specific antioxidant (PRDX2)) were mitochondrial proteins, three (ATP5B, MDH2, triosephosphate isomerase) were involved in energy generation, three (PRDX1, PRDX2, SELENBP1) were cellular antioxidants, and six (HSPD1, HSPA9B, PRDX1, PRDX2, PHB, VDACl) were stress-response proteins. Transmission electron microscopy revealed pathological alterations of mitochondrial ultrastructures even before the global colonocyte changes in the UC colon mucosa. PHB, an essential mitochondrial component protein, was down-expressed in the disease active as well as inactive colon mucosa from the patients of UC, indicative of an early event of mitochondrial changes during UC development. In contrast, aberrant activation of NFAT and ectopic expression of potential immunogenic proteins (tumor rejection antigen 1 and poliovirus receptor related protein 1) were found in the UC-diseased colon mucosa. Our findings suggest the implications of colonocyte mitochondrial dysfunction and perturbed mucosa immune regulation in the pathogenesis of UC and provide potential targets for the development of a new therapy.