Endoplasmic reticulum stress: implications for inflammatory bowel disease pathogenesis

Kaser, Arthur; Martı́nez-Naves, Eduardo; Blumberg, Richard S.

doi:10.1097/mog.0b013e32833a9ff1

Cited by 99 publications

(97 citation statements)

References 66 publications

(126 reference statements)

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“…Paneth cells, goblets cells, and other highly secretory cells are particularly prone to ER stress and therefore dependent on the UPR pathway to increase the size and protein processing function of the ER. 101 Mutations within the UPR, and environmental factors that create disturbances in the UPR, such as microbial products and inflammatory cytokines, have been shown to cause or perpetuate intestinal inflammation. 101 Autophagy, a lysosomal process, is triggered by cellular stress including ER stress.…”

Section: Specific Genes Related To Ibdmentioning

confidence: 99%

“…101 Mutations within the UPR, and environmental factors that create disturbances in the UPR, such as microbial products and inflammatory cytokines, have been shown to cause or perpetuate intestinal inflammation. 101 Autophagy, a lysosomal process, is triggered by cellular stress including ER stress. 97,101 Two variants of the autophagy protein, ATG16L1 and IRGM, have been discovered in association with CD.…”

Section: Specific Genes Related To Ibdmentioning

confidence: 99%

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Characterization of the Gastrointestinal Microbiota in Health and Inflammatory Bowel Disease

Cruz

Prideaux

Wagner

et al. 2012

Inflammatory Bowel Diseases

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The enteric bacterial flora play a key role in maintaining health. Inflammatory bowel disease is associated with quantitative and qualitative alterations in the microbiota. Early characterization of the microbiota involved culture-dependent techniques. The advent of metagenomic techniques, however, allows for structural and functional characterization using culture-independent methods. Changes in diversity, together with quantitative alterations in specific bacterial species, have been identified. The functional significance of these changes, and their pathogenic role, remain to be elucidated.

show abstract

Section: Specific Genes Related To Ibdmentioning

confidence: 99%

Section: Specific Genes Related To Ibdmentioning

confidence: 99%

Characterization of the Gastrointestinal Microbiota in Health and Inflammatory Bowel Disease

Cruz

Prideaux

Wagner

et al. 2012

Inflammatory Bowel Diseases

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“…A mouse model of severe gut inflammation demonstrated impaired UPR secondary to XBP1 deficiency (Kaser et al 2008). Paneth cell hypertrophy in ASD may reflect an inflammatory response to microbial and other environmental factors (Kaser et al 2010) associated with impaired UPR (Hodin et al 2011). We therefore believe that this function may be relevant to gastrointestinal disorders in general and in autism in particular.…”

Section: S65mentioning

confidence: 99%

Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells

Klein

Tamir

Hirschberg

et al. 2014

Cell Stress and Chaperones

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We have shown that oxytocin receptor (OTR) expression in neonatal rat enterocytes is robust from birth to weaning, but OTR function during this period is unknown. We previously reported that oxytocin (OT) stimulation of Caco2BB cells (enterocytes in vitro) inhibits the mammalian target of rapamycin complex 1 (mTORC1) signaling. The unfolded protein response (UPR) is known to protectively reduce translation during endoplasmic reticulum (ER) stress. Because the mTORC1 pathway is linked to cellular stress, we investigated markers of UPR in OT-stimulated Caco2BB cells. We report that OT modulates several factors involved in sensing and translation of ER stress. High OT (62.5 nM) reduced translation initiation factor 4E-BP1 phosphorylation (Ser65), which is known to inhibit cap-dependent translation via its rate-limiting eukaryotic translation initiation factor 4E (eIF4E). Importantly, high OT increased phosphorylation of eukaryotic translation initiation factor 2a (eIF2a) phosphoSer51, which inhibits eIF2a. High OT also increased protein kinase RNA-like endoplasmic reticulum kinase phosphorylation, a sensor of ER stress and a kinase of eIF2a. Both high and low OT activated inositol requiring enzyme1 (IRE1), which generates the transcription factor X-box binding protein 1 (XBP1) and induces the UPR. We also show that OT modulates XBP1 splicing and induces tribbles 3 (TRIB3; a negative regulator of Akt and protein involved in autophagy) and immunoglobulin binding protein (BiP; ER-chaperone). Taken together, these results indicate that OT modulates sensors of ER stress and autophagy. These findings support our hypothesis that transiently elevated OTR expression in neonatal gut may serve a protective function during a critical postnatal developmental period.

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“…This could occur as a result of co-factors such as smoking and/or dietary factors that could increase ER stress above the capacity of a normal UPR to resolve, genetic polymorphisms in one or more components of the UPR making the system less capable of responding to the ER stress, and/or environmentally-induced alterations in the UPR preventing a sufficiently robust UPR. An example of genetic polymorphisms in a UPR component that alters disease risk was recently reported in inflammatory bowel disease [60,71] . In this case, there was a fourfold increase in relatively rare genetic polymorphisms in patients with inflammatory bowel disease compared to controls.…”

Section: Discussionmentioning

confidence: 99%

Alcohol Abuse, Endoplasmic Reticulum Stress and Pancreatitis

Pandol¹,

Gorelick

Gerloff³

et al. 2010

Dig Dis

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Alcohol abuse is a common cause of both acute and chronic pancreatitis. There is a wide spectrum of pancreatic manifestations in heavy drinkers from no apparent disease in most individuals to acute inflammatory and necrotizing pancreatitis in a minority of individuals with some progressing to chronic pancreatitis characterized by replacement of the gland by fibrosis and chronic inflammation. Both smoking and African-American ethnicity are associated with increased risk of alcoholic pancreatitis. In this review we describe how our recent studies demonstrate that ethanol feeding in rodents causes oxidative stress in the endoplasmic reticulum (ER) of the digestive enzyme synthesizing acinar cell of the exocrine pancreas. This ER stress is attenuated by a robust unfolded protein response (UPR) involving X-box binding protein-1 (XBP1) in the acinar cell. When the UPR activation is prevented by genetic reduction in XBP1, ethanol feeding causes significant pathological responses in the pancreas. These results suggest that the reason most individuals who drink alcohol heavily do not get significant pancreatic disease is because the pancreas mounts an adaptive UPR to attenuate the ER stress that ethanol causes. We hypothesize that disease in the pancreas results when the UPR is insufficiently robust to alleviate the ER stress caused by alcohol abuse.

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Endoplasmic reticulum stress: implications for inflammatory bowel disease pathogenesis

Cited by 99 publications

References 66 publications

Characterization of the Gastrointestinal Microbiota in Health and Inflammatory Bowel Disease

Characterization of the Gastrointestinal Microbiota in Health and Inflammatory Bowel Disease

Oxytocin modulates markers of the unfolded protein response in Caco2BB gut cells

Alcohol Abuse, Endoplasmic Reticulum Stress and Pancreatitis

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