TNF a induced down regulation of CDX2 suppresses MEP1A expression in colitis.
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 a (TNF a) and finally to reveal if CDX2 is involved in a TNF a 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 a treated Caco 2 cells by reverse transcription polymerase chain reaction and with reporter gene assays, and the effect of anti TNF a 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 a 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 a stimulation. Finally, TNF a 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 a mediated down regulation of CDX2 can be related to suppressed expression of MEP1A during intestinal inflammation.
Biochimica et biophysica acta