title: Regulation of antiapoptotic and cytoprotective pathways in colonic epithelial cells in ulcerative colitis.
abstract: Ulcerative colitis is an inflammatory bowel disease involving the colon resulting in bloody diarrhea and increased risk of colorectal cancer in certain patient subgroups. Increased apoptosis in the epithelial cell layer causes increased permeability, especially during flares; this leads to translocation of luminal pathogens resulting in a continued inflammatory drive. The present work investigates how epithelial apoptosis is regulated in ulcerative colitis. The main results are that Fas mediated apoptosis is inhibited during flares of ulcerative colitis, probably by an upregulation of cellular inhibitor of apoptosis protein 2 (cIAP2) and cellular FLICE-like inhibitory protein. cIAP2 is upregulated in regenerative epithelial cells both in ulcerative colitis and in experimental intestinal wounds. Inhibition of cIAP2 decreases wound healing in vitro possibly through inhibition of migration. Altogether, it is shown that epithelial cells in ulcerative colitis responds to the hostile microenvironment by activation of cytoprotective pathways that tend to counteract the cytotoxic effects of inflammation. However, the present studies also show that epithelial cells produce increased amounts of reactive oxygen species during stimulation with tumor necrosis factor-α and interferon-γ resulting in DNA instability. The combined effect of increased DNA-instability and decreased apoptosis responses could lead to neoplasia.
authors.affiliation: a Department of Gastroenterology, Medical Section , Herlev Hospital, University of Copenhagen , Herlev , Denmark.
authors.forename: Jakob B
authors.initials: JB
authors.lastname: Seidelin
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D018938:Caco-2 Cells; D003093:Colitis, Ulcerative / Q000235:genetics*; D016207:Cytokines / Q000378:metabolism; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D007371:Interferon-gamma / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*; D015854:Up-Regulation; D014945:Wound Healing / Q000235:genetics*
chemical_list: D016207:Cytokines; D051034:Inhibitor of Apoptosis Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases
keywords: Apoptosis; DNA instability; cFLIP; cIAP2; inflammatory bowel disease; intestinal epithelium; ulcerative colitis