PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice
Wei Qiu, Bin Wu, Xinwei Wang, Monica E. Buchanan, Miguel D. Regueiro, Douglas J. Hartman, Robert E. Schoen, Jian Yu, Lin Zhang
Wei Qiu, Bin Wu, Xinwei Wang, Monica E. Buchanan, Miguel D. Regueiro, Douglas J. Hartman, Robert E. Schoen, Jian Yu, Lin Zhang
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Research Article Gastroenterology

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

Wei Qiu, Bin Wu, Xinwei Wang, Monica E. Buchanan, Miguel D. Regueiro, Douglas J. Hartman, Robert E. Schoen, Jian Yu, Lin Zhang

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Figure 2

Induction of PUMA in colonic mucosa after DSS treatment.

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Induction of PUMA in colonic mucosa after DSS treatment. WT and PUMA-KO ...
WT and PUMA-KO mice were treated with 5% DSS to induce colitis. (A) The expression of the indicated inflammatory cytokines in WT mice treated with DSS for 24 hours was analyzed by real-time RT-PCR. *P < 0.01 compared with the control. (B) PUMA mRNA expression in WT and PUMA-KO mice treated with DSS for 24 hours was analyzed by RT-PCR. (C) PUMA mRNA expression in WT mice treated with DSS for 24 hours was determined by real-time RT-PCR. (D) PUMA mRNA expression (dark dots) in WT mice with or without DSS treatment for 5 days was analyzed by RNA ISH (original magnification, ×400). Arrows indicate example PUMA-expressing cells. (E) PUMA protein expression in WT and PUMA-KO mice treated with DSS for 7 days was analyzed by Western blotting. Values in A and C were mean ± SD (n = 3 in each group).