PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice
Wei Qiu, … , Jian Yu, Lin Zhang
Wei Qiu, … , Jian Yu, Lin Zhang
Published April 1, 2011
Citation Information: J Clin Invest. 2011;121(5):1722-1732. https://doi.org/10.1172/JCI42917.
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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 5

TNBS-induced and PUMA-dependent colitis.

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TNBS-induced and PUMA-dependent colitis. WT and PUMA-KO mice were treate...
WT and PUMA-KO mice were treated with 100 mg/kg of TNBS to induce colitis. (A) PUMA mRNA expression in colonic mucosa of WT mice treated with TNBS for 12 or 24 hours was analyzed by real-time RT-PCR. (B) PUMA mRNA expression (dark dots) in WT mice with or without TNBS treatment for 3 days was analyzed by RNA ISH (original magnification, ×400). Arrows indicate example PUMA-expressing cells. (C) PUMA and p53 protein expression in WT mice after TNBS treatment for 3 days was determined by Western blotting. (D) H&E staining of colonic tissues from the mice treated with TNBS for 3 days (original magnification, ×200). (E) Histological damage in mice treated with TNBS for 3 days was scored after H&E staining as in D. (F) Length of the colonic ulcers in WT and PUMA-KO mice treated with TNBS for 3 days. (G) TUNEL (brown) staining of colonic tissues from mice treated with TNBS for 3 days (original magnification, ×200). Arrows indicate example TUNEL-positive cells. (H) The apoptotic index was calculated by counting TUNEL spots in 100 randomly selected crypts. Values in A, E, F, and H were mean ± SD (n = 3 in each group).