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

Mehmet Coskun; Anders Krüger Olsen; Thomas Lindebo Holm; Peter Helding Kvist; Ole Haagen Nielsen; Lene Buhl Riis; Jørgen Olsen; Jesper Thorvald Troelsen

doi:10.1016/j.bbadis.2012.01.012

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

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

26 Citations (Scopus)

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 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-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.

Original language	English
Journal	BBA General Subjects
Volume	1822
Issue number	6
Pages (from-to)	843-51
Number of pages	9
ISSN	0304-4165
DOIs	https://doi.org/10.1016/j.bbadis.2012.01.012
Publication status	Published - Jun 2012

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10.1016/j.bbadis.2012.01.012

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@article{967bbe3fc1fa4d6ca281c2cd56706b53,

title = "TNF-a-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 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-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 Haagen} and Riis, {Lene Buhl} and J{\o}rgen Olsen and Troelsen, {Jesper Thorvald}",

year = "2012",

month = jun,

doi = "10.1016/j.bbadis.2012.01.012",

language = "English",

volume = "1822",

pages = "843--51",

journal = "BBA General Subjects",

issn = "0304-4165",

publisher = "Elsevier",

number = "6",

}

TY - JOUR

T1 - TNF-a-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 Haagen

AU - Riis, Lene Buhl

AU - Olsen, Jørgen

AU - Troelsen, Jesper Thorvald

PY - 2012/6

Y1 - 2012/6

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 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-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 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-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

C2 - 22326557

SN - 0304-4165

VL - 1822

SP - 843

EP - 851

JO - BBA General Subjects

JF - BBA General Subjects

IS - 6

ER -

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

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