Increased Enterocyte Apoptosis in Inflamed Areas of Crohn's Disease

Sabatino, Antonio Di; Ciccocioppo, Rachele; Luinetti, Ombretta; Ricevuti, L.; Morera, R.; Cifone, Maria Grazia; Solcia, Enrico; Corazza, Gino Roberto

doi:10.1007/s10350-004-6802-z

Cited by 140 publications

(109 citation statements)

References 47 publications

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“…Increased IEC apoptosis has been reported in patients with UC and CD (6)(7)(8) as well as in murine models of colitis (9,10). Excess IEC apoptosis causes focal disruption of the mucosal barrier, leading to invasion of luminal antigens and bacteria, and proinflammatory cytokines induced in this process can cause more IEC apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

et al. 2013

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The inhibitory effects of vitamin D on colitis have been previously documented. Global vitamin D receptor (VDR) deletion exaggerates colitis, but the relative anticolitic contribution of epithelial and nonepithelial VDR signaling is unknown. Here, we showed that colonic epithelial VDR expression was substantially reduced in patients with Crohn's disease or ulcerative colitis. Moreover, targeted expression of human VDR (hVDR) in intestinal epithelial cells (IECs) protected mice from developing colitis. In experimental colitis models induced by 2,4,6-trinitrobenzenesulfonic acid, dextran sulfate sodium, or CD4 + CD45RB hi T cell transfer, transgenic mice expressing hVDR in IECs were highly resistant to colitis, as manifested by marked reductions in clinical colitis scores, colonic histological damage, and colonic inflammation compared with WT mice. Reconstitution of Vdr-deficient IECs with the hVDR transgene completely rescued Vdr-null mice from severe colitis and death, even though the mice still maintained a hyperresponsive Vdr-deficient immune system. Mechanistically, VDR signaling attenuated PUMA induction in IECs by blocking NF-κB activation, leading to a reduction in IEC apoptosis. Together, these results demonstrate that gut epithelial VDR signaling inhibits colitis by protecting the mucosal epithelial barrier, and this anticolitic activity is independent of nonepithelial immune VDR actions.

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Section: Introductionmentioning

confidence: 99%

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

et al. 2013

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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). Induction of IEC apoptosis has also been described in a number of studies using murine colitis models (6)(7)(8).…”

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.

163

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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“…1D). Ulceration is very closely associated with apoptosis of epithelial cells during IBD (25,26), and we thought to examine the infected colons for apoptosis. Infected P KO mice showed more TUNEL + colonic epithelial cells compared with WT controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Properdin Provides Protection from Citrobacter rodentium–Induced Intestinal Inflammation in a C5a/IL-6–Dependent Manner

Jain

Cao

Thomas

et al. 2015

The Journal of Immunology

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Citrobacter rodentium is an attaching and effacing mouse pathogen that models enteropathogenic and enterohemorrhagic Escherichia coli in humans. The complement system is an important innate defense mechanism; however, only scant information is available about the role of complement proteins during enteric infections. In this study, we examined the impact of the lack of properdin, a positive regulator of complement, in C. rodentium–induced colitis. Following infection, properdin knockout (PKO) mice had increased diarrhea and exacerbated inflammation combined with defective epithelial cell–derived IL-6 and greater numbers of colonizing bacteria. The defect in the mucosal response was reversed by administering exogenous properdin to PKO mice. Then, using in vitro and in vivo approaches, we show that the mechanism behind the exacerbated inflammation of PKO mice is due to a failure to increase local C5a levels. We show that C5a directly stimulates IL-6 production from colonic epithelial cells and that inhibiting C5a in infected wild-type mice resulted in defective epithelial IL-6 production and exacerbated inflammation. These outcomes position properdin early in the response to an infectious challenge in the colon, leading to complement activation and C5a, which in turn provides protection through IL-6 expression by the epithelium. Our results unveil a previously unappreciated mechanism of intestinal homeostasis involving complement, C5a, and IL-6 during bacteria-triggered epithelial injury.

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Increased Enterocyte Apoptosis in Inflamed Areas of Crohn's Disease

Cited by 140 publications

References 47 publications

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis

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

Properdin Provides Protection from Citrobacter rodentium–Induced Intestinal Inflammation in a C5a/IL-6–Dependent Manner

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