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

    Resumé

    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, Mehmet ; Olsen, Anders Krüger ; Holm, Thomas Lindebo ; Kvist, Peter Helding ; Nielsen, Ole Hagen ; Riis, Lene Buhl ; Olsen, Jørgen ; Troelsen, Jesper. / TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis. I: B B A - Molecular Basis of Disease. 2012 ; Bind 1822, Nr. 6. s. 843-851.
    @article{8e505631eb0e4931acadeeb50bc57eec,
    title = "TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis",
    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.",
    author = "Mehmet Coskun and Olsen, {Anders Kr{\"u}ger} and Holm, {Thomas Lindebo} and Kvist, {Peter Helding} and Nielsen, {Ole Hagen} and Riis, {Lene Buhl} and J{\o}rgen Olsen and Jesper Troelsen",
    year = "2012",
    doi = "10.1016/j.bbadis.2012.01.012",
    language = "English",
    volume = "1822",
    pages = "843--851",
    journal = "B B A - Molecular Basis of Disease",
    issn = "0925-4439",
    publisher = "Elsevier BV",
    number = "6",

    }

    Coskun, M, Olsen, AK, Holm, TL, Kvist, PH, Nielsen, OH, Riis, LB, Olsen, J & Troelsen, J 2012, 'TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis', B B A - Molecular Basis of Disease, bind 1822, nr. 6, s. 843-851. https://doi.org/10.1016/j.bbadis.2012.01.012

    TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis. / Coskun, Mehmet; Olsen, Anders Krüger; Holm, Thomas Lindebo; Kvist, Peter Helding; Nielsen, Ole Hagen ; Riis, Lene Buhl; Olsen, Jørgen; Troelsen, Jesper.

    I: B B A - Molecular Basis of Disease, Bind 1822, Nr. 6, 2012, s. 843-851.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - TNF-α-induced down-regulation of CDX2 suppresses MEP1A expression in colitis

    AU - Coskun, Mehmet

    AU - Olsen, Anders Krüger

    AU - Holm, Thomas Lindebo

    AU - Kvist, Peter Helding

    AU - Nielsen, Ole Hagen

    AU - Riis, Lene Buhl

    AU - Olsen, Jørgen

    AU - Troelsen, Jesper

    PY - 2012

    Y1 - 2012

    N2 - 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.

    AB - 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.

    U2 - 10.1016/j.bbadis.2012.01.012

    DO - 10.1016/j.bbadis.2012.01.012

    M3 - Journal article

    VL - 1822

    SP - 843

    EP - 851

    JO - B B A - Molecular Basis of Disease

    JF - B B A - Molecular Basis of Disease

    SN - 0925-4439

    IS - 6

    ER -