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

Mehmet Coskun, Anders Krüger Olsen, Thomas Lindebo Holm, Peter Helding Kvist, Ole Hagen Nielsen, Lene Buhl Riis, Jørgen Olsen, Jesper Troelsen

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Abstract

    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 several inflammatory bowel disease- (IBD-) susceptibility genes, including MEP1A. The aim was to investigate the expression of CDX2 and meprin 1A (MEP1A) in colitis; to assess if they are regulated by tumor necrosis factor-α (TNF-α), and finally to reveal if CDX2 is involved in a TNF-α-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-α-treated Caco-2 cells by reverse transcription-polymerase chain reaction and with reporter gene assays, and the effect of anti-TNF-α 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-α 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-α stimulation. Finally, TNF-α 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-α-mediated down-regulation of CDX2 can be related to suppressed expression of MEP1A during intestinal inflammation.
    OriginalsprogEngelsk
    TidsskriftB B A - Molecular Basis of Disease
    Vol/bind1822
    Udgave nummer6
    Sider (fra-til)843-851
    Antal sider9
    ISSN0925-4439
    DOI
    StatusUdgivet - 2012

    Citer dette

    Coskun, M., Olsen, A. K., Holm, T. L., Kvist, P. H., Nielsen, O. H., Riis, L. B., Olsen, J., & Troelsen, J. (2012). TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis. B B A - Molecular Basis of Disease, 1822(6), 843-851. https://doi.org/10.1016/j.bbadis.2012.01.012