Recent insights into the integration of the intestinal epithelium within the mucosal environment in health and disease

Blumberg, Richard S.; Li, Linheng; Nusrat, Asma; Parkos, Charles A.; Rubin, Deborah C.; Carrington, Jill L.

doi:10.1038/mi.2008.29

Cited by 15 publications

(21 citation statements)

References 38 publications

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“…This is highly significant given the strategic location of the epithelium between the two major factors that determine intestinal inflammation; the luminal microbiota and the immunologic tone of mucosal tissues in response to the microbiota. 1 These studies suggest that XBP1 may regulate the ability of the intestinal epithelium to both regulate and sense the composition of luminal microbiota. ER stress may thus be a major determinant of luminal microbial epithelial interactions and inflammatory tone and an important factor in determining whether homeostasis versus inflammation will occur.…”

Section: Conclusion and Modelmentioning

confidence: 99%

“…1 This relationship between the microbiota, epithelium, and hematopoietic system is of central importance to understanding mucosal homeostasis, on the one hand, and inflammation, on the other. Over the past several decades, it has become increasingly recognized that the epithelium can be an active participant in the immune system.…”

Section: Introductionmentioning

confidence: 99%

“…Over the past several decades, it has become increasingly recognized that the epithelium can be an active participant in the immune system. 1 Although it has been well known for some time that the epithelium can both respond to and secrete a wide variety of immune mediators, over the past several years it has become increasingly recognized that the epithelium can integrate apical signals from the lumenal microbiota and basal signals from the hematopoietic system. 2 Important studies from the groups of Cerutti and colleagues, 3 Rescigno and colleagues, 4 and Artis and colleagues 5 have, for example, shown how epithelial cells can respond to luminal microbial signals and condition dendritic cells and consequently lymphocytes to elicit immune functions in particular.…”

Section: Introductionmentioning

confidence: 99%

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Endoplasmic reticulum stress and intestinal inflammation

2010

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The intestinal epithelial cell (IEC) is increasingly recognized to play a prominent role as an important intermediary between the commensal microbiota and the intestinal immune system. Moreover, it is now recognized that intestinal inflammation in inflammatory bowel disease (IBD) may arise primarily from IEC dysfunction due to unresolved endoplasmic reticulum (ER) stress as a consequence of genetic disruption of X box binding protein-1 function. In addition to primary (genetic) abnormalities of the unfolded protein response, a variety of secondary (inflammation and environmental) factors are also likely to be important regulators of ER stress. ER stress pathways are also well known to regulate (and be regulated by) autophagy pathways. Therefore, the host’s ability to manage ER stress is likely to be a major pathway in the pathogenesis of intestinal inflammation that arises primarily from the IEC. Herein we discuss ER stress in the IEC as both an originator and perpetuator of intestinal inflammation in IBD.

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Section: Conclusion and Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endoplasmic reticulum stress and intestinal inflammation

2010

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“…They have to deal with the complex situation where they absorb nutrients and water, and also protect the host from commensal microbes, pathogens and toxic compounds. Various specific adaptations, such as tight junctions and microfolds, as well as specialized IECs such as goblet cells and Paneth cells, enable these cells to carry out their complex task [1].…”

Section: Introductionmentioning

confidence: 99%

Impeded protein folding and function in active inflammatory bowel disease

Deuring

Peppelenbosch

Kuipers

et al. 2011

Biochemical Society Transactions

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The intestinal tract is covered by a total of 300 square metres of IECs (intestinal epithelial cells) that covers the entire intestinal mucosa. For protection against luminal xenobiotics, pathogens and commensal microbes, these IECs are equipped with membrane-bound transporters as well as the ability to secrete specific protective proteins. In patients with active IBD (inflammatory bowel disease), the expression of these proteins, e.g. ABC (ATP-binding cassette) transporters such as ABCG2 (ABC transporter G2) and defensins, is decreased, thereby limiting the protection against various luminal threats. Correct ER (endoplasmic reticulum)-dependent protein folding is essential for the localization and function of secreted and membrane-bound proteins. Inflammatory triggers, such as cytokines and nitric oxide, can impede protein folding, which causes the accumulation of unfolded proteins inside the ER. As a result, the unfolded protein response is activated which can lead to a cellular process named ER stress. The protein folding impairment affects the function and localization of several proteins, including those involved in protection against xenobiotics. In the present review, we discuss the possible inflammatory pathways affecting protein folding and eventually leading to IEC malfunction in patients with active IBD.

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“…Intestinal epithelial cells (IECs) lie at the interface between intestinal microbes and lamina propria hematopoietic cells, suggesting that they play a key role in intestinal mucosal homeostasis (Blumberg et al, 2008). The intestinal epithelium consists of a mucosal barrier, which isolates the host from the hostile luminal pathogens presented by intestinal microbes (Kagnoff and Eckmann, 1997).…”

Section: Introductionmentioning

confidence: 99%

Fexofenadine Regulates Nuclear Factor-κB Signaling and Endoplasmic Reticulum Stress in Intestinal Epithelial Cells and Ameliorates Acute and Chronic Colitis in Mice

Koh

Kim

et al. 2014

J Pharmacol Exp Ther

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The aim of this study was to evaluate the effect of fexofenadine on intestinal inflammation. HCT116 and COLO205 cells were pretreated with fexofenadine and then stimulated with tumor necrosis factor (TNF)-a. Interleukin (IL)-8 expression was determined by real-time reverse-transcription polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay. DNA-binding activity of nuclear factor-kB was assessed by electrophoretic mobility shift assay. The molecular markers of endoplasmic reticulum (ER) stress were evaluated by Western blot analysis and PCR. In the acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days with or without fexofenadine. IL-10 2/2 mice were used to evaluate the effect of fexofenadine on chronic colitis. Fexofenadine significantly inhibited the upregulated expression of IL-8 in HCT116 and COLO205 cells stimulated with TNF-a. Fexofenadine suppressed nuclear factor-kB DNA-binding activity. C/EBP homologous protein mRNA expression was enhanced in the presence of TNF-a, and it was dampened by pretreatment of fexofenadine. In addition, the induction of ER stress markers caspase-12 and p-eukaryotic initiation factor 2 (eIF2)-a was significantly suppressed by the pretreatment of fexofenadine. Administration of fexofenadine significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histology. In addition, the DSS-induced phospho-IkB kinase activation was significantly decreased in fexofenadinepretreated mice. Finally, fexofenadine significantly reduced the severity of colitis and the immunoreactivity of caspase-12 and p-eIF2-a in IL-10 2/2 mice as compared with controls. These results suggest that fexofenadine is a potential therapeutic agent for the treatment of inflammatory bowel disease.

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Recent insights into the integration of the intestinal epithelium within the mucosal environment in health and disease

Cited by 15 publications

References 38 publications

Endoplasmic reticulum stress and intestinal inflammation

Endoplasmic reticulum stress and intestinal inflammation

Impeded protein folding and function in active inflammatory bowel disease

Fexofenadine Regulates Nuclear Factor-κB Signaling and Endoplasmic Reticulum Stress in Intestinal Epithelial Cells and Ameliorates Acute and Chronic Colitis in Mice

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