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 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.

• Authors: Mehmet Coskun, Anders Krüger Olsen, Thomas Lindebo Holm, Peter Helding Kvist, Ole Haagen Nielsen, Lene Buhl Riis, Jørgen Olsen, Jesper Thorvald Troelsen
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1822 Issue 6 Pg. 843-51 (Jun 2012) ISSN: 0006-3002 [Print] Netherlands
• PMID: 22326557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Elsevier B.V. All rights reserved.

Chemical References

• Antibodies, Monoclonal
• CDX2 Transcription Factor
• CDX2 protein, human
• Homeodomain Proteins
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Dextran Sulfate
• Infliximab
• Metalloendopeptidases
• meprin A

Topics

• Adult
• Animals
• Antibodies, Monoclonal (pharmacology)
• CDX2 Transcription Factor
• Cell Line
• Chromatin Immunoprecipitation
• Colitis, Ulcerative (chemically induced, genetics, metabolism, pathology)
• Dextran Sulfate
• Female
• Homeodomain Proteins (biosynthesis, genetics)
• Humans
• Inflammatory Bowel Diseases (genetics, metabolism, pathology)
• Infliximab
• Intestinal Mucosa (metabolism)
• Male
• Metalloendopeptidases (biosynthesis, genetics)
• Mice
• Middle Aged
• RNA, Messenger (genetics, metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism)