Positive Role of CCAAT/Enhancer-Binding Protein Homologous Protein, a Transcription Factor Involved in the Endoplasmic Reticulum Stress Response in the Development of Colitis

Namba, Takushi; Tanaka, Ken Ichiro; Ito, Yosuke; Ishihara, Takeshi; Hoshino, Tatsuya; Gotoh, Tomomi; Endo, Motoyoshi; Sato, Keizo; Mizushima, Tohru

doi:10.2353/ajpath.2009.080864

Cited by 103 publications

(99 citation statements)

References 57 publications

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“…Recent evidence points to a role of CHOP in various inflammatory diseases, such as LPS-induced lung damage [10,11], chemically induced pancreatitis [13] and experimental colitis [12]. Here, we demonstrate that CHOP is indeed central in the inflammatory response of liver, fat and macrophages, as peritoneal macrophages from Chop −/− mice exhibit a blunted inflammatory response to LPS.…”

Section: Discussionmentioning

confidence: 65%

“…Data are shown as the means±SEM (n08). ** p<0.01 and *** p<0.001 vs WT mice stimulatory mechanisms, such as macrophage infiltration via induction of macrophage-1 antigen (MAC-1), reactive oxygen species (ROS) production via ER oxidase 1α (ERO1α) and IL-1β production via caspase-11, all resulting in mucosal cell apoptosis [12]. Finally, it has been demonstrated that CHOP is an inhibitor of the wingless-Int (WNT) signalling pathway and is necessary for normal bone development as Chop overexpression induced osteopenia [16].…”

Section: Introductionmentioning

confidence: 99%

“…Progressive hyperglycaemia in the Akita mouse, a model spontaneously developing hyperglycaemia with reduced beta cell mass [7], is accompanied by Chop induction and beta cell apoptosis, but deletion of Chop delayed onset of diabetes in heterozygous Akita mice [8]. CHOP is also involved in the development of obesity [9] and regulation of inflammation [10][11][12][13]. Lung damage induced by lipopolysaccharide (LPS) treatment is attenuated in Chop −/− mice, suggesting that the ER-stress pathway involving CHOP is activated and displays a role in the pathogenesis of septic shock lung.…”

Section: Introductionmentioning

confidence: 99%

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Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

et al. 2012

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Aims/hypothesis Endoplasmic reticulum (ER) stress has been implicated in the development of type 2 diabetes, via effects on obesity, insulin resistance and pancreatic beta cell health. C/EBP homologous protein (CHOP) is induced by ER stress and has a central role in apoptotic execution pathways triggered by ER stress. The aim of this study was to characterise the role of CHOP in obesity and insulin resistance.Methods Metabolic studies were performed in Chop −/− and wild-type C57Bl/6 mice, and included euglycaemichyperinsulinaemic clamps and indirect calorimetry. The inflammatory state of liver and adipose tissue was determined by quantitative RT-PCR, immunohistology and macrophage cultures. Viability and absence of ER stress in islets of Langerhans was determined by electron microscopy, islet culture and quantitative RT-PCR. Results Systemic deletion of Chop induced abdominal obesity and hepatic steatosis. Despite marked obesity, Chop −/− mice had preserved normal glucose tolerance and insulin sensitivity. This discrepancy was accompanied by lower levels of pro-inflammatory cytokines and less infiltration of immune cells into fat and liver. Conclusions/interpretation These observations suggest that insulin resistance is not induced by fat accumulation per se, but rather by the inflammation induced by ectopic fat. CHOP may play a key role in the crosstalk between excessive fat deposition and induction of inflammation-mediated insulin resistance.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

et al. 2012

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“…The proinflammatory effect of CHOP in beta cells may require a second signal, provided by cytokines, since CHOP induction by CPA does not amplify NF-κB activation stimulated by a low concentration of IL-1β [20]. The role of CHOP in inflammatory responses (including chemokine and cytokine production) has been observed in different disease models, including myocardial inflammation [47], lung damage induced by LPS [48], inflammatory bowel disease [49] and obesity [15].…”

Section: Signal-transduction Of Upr-induced Islet Inflammationmentioning

confidence: 99%

Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

2012

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Protein synthesis is increased by several-fold in stimulated pancreatic beta cells. Synthesis and folding of (pro)insulin takes place in the endoplasmic reticulum (ER), and beta cells trigger the unfolded protein response (UPR) to upgrade the functional capacity of the ER. Prolonged or excessive UPR activation contributes to beta cell dysfunction and death in type 2 diabetes, but there is another side of the UPR that may be of particular relevance for autoimmune type 1 diabetes, namely, the crosstalk between the UPR and innate immunity/inflammation. Recent evidence, discussed in this review, indicates that both saturated fats and inflammatory mediators such as cytokines trigger the UPR in pancreatic beta cells. The UPR potentiates activation of nuclear factor κB, a key regulator of inflammation. Two branches of the UPR, namely IRE1/XBP1s and PERK/ATF4/CHOP, mediate the UPR-induced sensitisation of pancreatic beta cells to the proinflammatory effects of cytokines. This can contribute to the upregulation of local inflammatory mechanisms and the aggravation of insulitis. The dialogue between the UPR and inflammation may provide an explanation for the parallel increase in the prevalence of childhood obesity and type 1 diabetes.

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“…In the acute model for colitis elicited by dextran sulfate sodium (DSS), increased numbers of apoptotic bodies and TUNEL-positive colonocytes have been identified, and genetic ablation of apoptotic regulators protects mice from DSS-induced colitis. 5,7,8 Therefore, inhibition of intestinal epithelial apoptosis appears to be a promising therapeutic strategy to prevent barrier disruption.…”

mentioning

confidence: 99%

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

Laukens

Devisscher

Bossche

et al. 2014

Laboratory Investigation

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Ulcerative colitis (UC) is characterized by increased epithelial cell death and subsequent breakdown of the intestinal epithelial barrier, which perpetuates chronic intestinal inflammation. Since fecal bile acid dysmetabolism is associated with UC and tauroursodeoxycholic acid (TUDCA) has been shown to improve murine colitis, we evaluated the effect of TUDCA on intestinal epithelial cell death in a mouse model of UC-like barrier dysfunction elicited by dextran sulfate sodium (DSS). We identified the prevention of colonic caspase-3 induction, a key proapoptotic marker which was also over-activated in UC, as the earliest event resulting in a clear clinical benefit. Whereas vehicle-treated mice showed a cumulative mortality of 40%, all TUDCA-treated mice survived the DSS experiment during a 14-day follow-up period. In line with a barrier protective effect, TUDCA decreased bacterial translocation to the spleen and stimulated mucin production. Similarly, TUDCA inhibited lipopolysaccharide-induced intestinal permeability and associated enterocyte apoptosis. The anti-apoptotic effect was confirmed in vitro by a dose-dependent inhibition of both receptor-dependent (using tumor necrosis factor and Fas ligand) and receptor-independent (staurosporine) caspase-3 induction in HT29 colonic epithelial cells. These data imply that caspase-3 activation is an early marker of colitis that is prevented by TUDCA treatment. These data, together with the previously reported beneficial effect in colitis, suggest that TUDCA could be an add-on strategy to current immunosuppressive treatment of UC patients.

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Positive Role of CCAAT/Enhancer-Binding Protein Homologous Protein, a Transcription Factor Involved in the Endoplasmic Reticulum Stress Response in the Development of Colitis

Cited by 103 publications

References 57 publications

Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance

Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

Tauroursodeoxycholic acid inhibits experimental colitis by preventing early intestinal epithelial cell death

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