Comparative proteomic studies on the pathogenesis of human ulcerative colitis.
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, VDAC1) 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.
Hsieh
Sen-Yung
SY
Clinical Proteomics Center, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan. siming@adm.cgmh.org.tw
Shih
Tsung-Chieh
TC
Yeh
Chien-Yuh
CY
Lin
Chun-Jung
CJ
Chou
Yun-Ying
YY
Lee
Ying-Shiung
YS
D000328:Adult; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D008297:Male; D000091402:Prohibitins; D020543:Proteome / Q000378:metabolism* / Q000648:ultrastructure; D040901:Proteomics
C000717328:PHB protein, human; D000091402:Prohibitins; D020543:Proteome