title: PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice.
abstract: Intestinal epithelial cell (IEC) apoptosis contributes to the development of ulcerative colitis (UC), an inflammatory bowel disease (IBD) that affects the colon and rectum. Therapies that target the inflammatory cytokine TNF have been found to inhibit IEC apoptosis in patients with IBD, although the mechanism of IEC apoptosis remains unclear. We therefore investigated the role of p53-upregulated modulator of apoptosis (PUMA), a p53 target and proapoptotic BH3-only protein, in colitis and IEC apoptosis, using patient samples and mouse models of UC. In UC patient samples, PUMA expression was elevated in colitis tissues relative to that in uninvolved tissues, and the degree of elevation of PUMA expression correlated with the severity of colitis and the degree of apoptosis induction. In mice, PUMA was markedly induced in colonic epithelial cells following induction of colitis by either dextran sulfate sodium salt (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). The induction of PUMA was p53-independent but required NF-κB. Absence of PUMA, but neither absence of p53 nor that of another BH3-only protein (Bid), relieved DSS- and TNBS-induced colitis and inhibited IEC apoptosis. Furthermore, treating mice with infliximab (Remicade), a clinically used TNF-specific antibody, suppressed DSS- and TNBS-induced PUMA expression and colitis. These results indicate that PUMA induction contributes to the pathogenesis of colitis by promoting IEC apoptosis and suggest that PUMA inhibition may be an effective strategy to promote mucosal healing in patients with UC.
authors.affiliation: University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
authors.forename: Bin
authors.initials: B
authors.lastname: Wu
authors.forename: Xinwei
authors.initials: X
authors.lastname: Wang
authors.forename: Monica E
authors.initials: ME
authors.lastname: Buchanan
authors.forename: Miguel D
authors.initials: MD
authors.lastname: Regueiro
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hartman
authors.forename: Robert E
authors.initials: RE
authors.lastname: Schoen
authors.forename: Jian
authors.initials: J
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002648:Child; D003093:Colitis, Ulcerative / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D000069285:Infliximab; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016328:NF-kappa B; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D000069285:Infliximab