Regulation of apoptosis during homeostasis and disease in the intestinal epithelium

Edelblum, Karen L.; Yan, Fang; Yamaoka, Toshimitsu; Polk, D. Brent

doi:10.1097/01.mib.0000217334.30689.3e

Cited by 168 publications

(136 citation statements)

References 157 publications

(260 reference statements)

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“…Apoptosis results in the deletion of epithelial cells from the intestinal mucosa with an accompanying inflammatory response [12,13]. Cells undergoing apoptosis are ingested by phagocytic cells or shed into the intestinal lumen.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

2008

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Enterotoxigenic Bacteroides fragilis produces an approximately 20-kDa heat-labile enterotoxin (BFT) that plays an essential role in generating mucosal inflammation. Although it is well known that proinflammatory signals are expressed in BFT-stimulated intestinal epithelial cells, cell death processes have not been elucidated. BFT induced apoptosis in HT-29 cells, but the apoptosis was first apparent 36 h after stimulation. During the early period of BFT stimulation, expression of cellular inhibitor of apoptosis protein-2 (c-IAP2) increased, and inhibition of c-IAP2 augmented the apoptotic cell death. Inhibition of BFT-induced COX-2 expression decreased prostaglandin E 2 (PGE 2 ) production, which led not only to a decrease of c-IAP2 activity but also to an enhancement of DNA fragmentation in the early period of BFT stimulation. Furthermore, apoptosis inhibition through PGE 2 and c-IAP2 was mainly regulated by a p38 mitogen-activated protein kinase (MAPK). These results suggest that the inhibition of apoptosis may be mediated by a sequential pathway, including MAPK, COX-2, PGE 2 and c-IAP2, in the early period of stimulation. The delay in the onset of epithelial cell apoptosis after enterotoxigenic B. fragilis infection may be important to the host since it can provides sufficient time for epithelial cells to generate signals for the activation of mucosal inflammation and it may increase the chances of bacterial colonization.

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Section: Introductionmentioning

confidence: 99%

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

2008

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“…Although the pathogenesis of IBD remains unclear, a number of studies have suggested a role of abnormal apoptosis in the intestinal epithelial cells (IECs), resulting from increased cytokine production, such as TNF, IL, and interferon family members (2). Increased IEC apoptosis has been detected at the acute inflammatory sites in UC (3,4) and CD patients (5).…”

Section: Introductionmentioning

confidence: 99%

PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

Qiu

Wu²,

Wang³

et al. 2011

J. Clin. Invest.

167

161

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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.

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“…Consequently, the rate of intestinal epithelial cell apoptosis is central to the maintenance of an intact intestinal barrier. 64 The rate of intestinal epithelial cell apoptosis is increased in IBD leading to a loss of intestinal barrier function with subsequent exposure of the mucosal immune system to the microbiota. 65 Initial studies into the protective effects of pharmacologic hydroxylase inhibition revealed an antiapoptotic role for the pan-hydroxylase inhibitor DMOG in DSS colitis.…”

Section: Protective Mechanisms Of Hydroxylase Inhibitors In Ibd Inhibmentioning

confidence: 99%

Hydroxylases as therapeutic targets in inflammatory bowel disease

Cummins

Doherty

Taylor

2013

Laboratory Investigation

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Inflammatory bowel disease (IBD) is a common and debilitating clinical disorder comprising ulcerative colitis and Crohn's disease. IBD occurs when inappropriate immunological activity in the intestinal mucosa results in epithelial barrier dysfunction leading to exposure of the mucosal immune system to luminal antigenic material. This in turn results in the cycles of inflammation and further barrier dysfunction which underlie disease progression. Although significant therapeutic advances have been made over the last decade, current immunosuppressive and anti-inflammatory treatments for IBD have significant limitations due to lack of treatment response in some patients and adverse effects, including increased risk of infection and malignancy. Recent studies using experimental models of IBD have identified that intracellular hydroxylases, a group of enzymes responsible for oxygen sensing and activation of adaptive transcriptional responses to hypoxia may represent a new class of therapeutic targets in IBD. Hydroxylase inhibitors are effective in ameliorating symptoms of colitis at least in part through the promotion of intestinal epithelial barrier function. The mechanism of this protection is due to activation of hypoxia-sensitive transcription factors, including the hypoxiainducible factor (HIF) and nuclear factor kappa-B (NF-kB), which activate specific epithelial barrier-protective transcriptional programs. In this review, the mechanism(s) of action and the therapeutic potential of small molecule hydroxylase inhibitors for the treatment of IBD will be discussed.

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Regulation of apoptosis during homeostasis and disease in the intestinal epithelium

Cited by 168 publications

References 157 publications

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

Inhibition of apoptosis in Bacteroides fragilis enterotoxin‐stimulated intestinal epithelial cells through the induction of c‐IAP‐2

PUMA-mediated intestinal epithelial apoptosis contributes to ulcerative colitis in humans and mice

Hydroxylases as therapeutic targets in inflammatory bowel disease

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