TNF-伪-induced down-regulation of CDX2 suppresses MEP1A expression in colitis

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• 作者：Mehmet Coskun^a ; ^b ; ^{mehmet.coskun@regionh.dk} ; Anders Krü ; ger Olsen^b ; ^c ; Thomas Lindebo Holm^d ; Peter Helding Kvist^d ; Ole Haagen Nielsen^a ; Lene Buhl Riis^e ; Jø ; rgen Olsen^b ; Jesper Thorvald Troelsen^f
• 关键词：CD ; Crohn's disease ; CDX2 ; Caudal-related homeobox transcription factor 2 ; ChIP ; chromatin immunoprecipitation ; CK20 ; cytokeratin 20 ; CLDN2 ; claudin-2 ; DAI ; disease activity index ; DSS ; dextran sodium sulfate ; GAPDH ; glyceraldehyde 3-phosphate dehydrogena
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2012
• 期刊代码：19_09254439
• 类别：bio
• 出版时间：June, 2012
• 卷：1822
• 期：6
• 页码：843-851
• 文件大小：953 K

摘要

Background/aims: High levels of pro-inflammatory cytokines are linked to inflammatory bowel disease (IBD). The transcription factor Caudal-related homeobox transcription factor 2 (CDX2) plays a crucial role in differentiation of intestinal epithelium and regulates IBD-susceptibility genes, including meprin 1A (MEP1A). The aim was to investigate the expression of CDX2 and MEP1A in colitis; to assess if they are regulated by tumor necrosis factor-伪 (TNF-伪), and finally to reveal if CDX2 is involved in a TNF-伪-induced down-regulation of MEP1A. Methods: Expression of CDX2 and MEP1A was investigated in colonic biopsies of ulcerative colitis (UC) patients and in dextran sodium sulfate (DSS)-induced colitis. CDX2 protein expression was investigated by immunoblotting and immunohistochemical procedures. CDX2 and MEP1A regulation was examined in TNF-伪-treated Caco-2 cells by reverse transcription-polymerase chain reaction and with reporter gene assays, and the effect of anti-TNF-伪 treatment was assessed using infliximab. Finally, in vivo CDX2-DNA interactions were investigated by chromatin immunoprecipitation. Results: The CDX2 and MEP1A mRNA expression was significantly decreased in active UC patients and in DSS-colitis. Colonic biopsy specimens from active UC showed markedly decreased CDX2 staining. TNF-伪 treatment diminished the CDX2 and MEP1A mRNA levels, a decrease which, was counteracted by infliximab treatment. Reporter gene assays showed significantly reduced CDX2 and MEP1A activity upon TNF-伪 stimulation. Finally, TNF-伪 impaired the ability of CDX2 to interact and activate its own, as well as the MEP1A expression. Conclusions: The present results indicate that a TNF-伪-mediated down-regulation of CDX2 can be related to suppressed expression of MEP1A during intestinal inflammation.