Linking Immunity, Epigenetics, and Cancer in Inflammatory Bowel Disease

Däbritz, Jan; Menheniott, Trevelyan R.

doi:10.1097/mib.0000000000000063

Cited by 42 publications

(34 citation statements)

References 225 publications

(276 reference statements)

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“…1) 23,46) . In addition, ROS and RNI species are released by immune cells upon stimulation with inflammatory cytokines, including IL-1β and IL-6, as well as by commensal bacteria in the lumen 23) . Lactobacilli and Bifidobacteria can generate large amounts of nitric oxide from nitrite, and dietary supplementation with nitrate may increase nitric oxide production 47,48) .…”

Section: Microbiota-mediated Epigenetic Regulation Of Intestinal Epitmentioning

confidence: 99%

“…The proinflammatory cytokine Interluekin-1β (IL-1β), secreted from immune cells within the lamina propria, also stimulates DNMT1 activity in a nitric oxide (NO)-dependent manner through upregulation of inducible nitric oxide synthase (iNOS) in IECs ( Fig. 1) 23,46) . In addition, ROS and RNI species are released by immune cells upon stimulation with inflammatory cytokines, including IL-1β and IL-6, as well as by commensal bacteria in the lumen 23) .…”

Section: Microbiota-mediated Epigenetic Regulation Of Intestinal Epitmentioning

confidence: 99%

“…Reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) trigger oxidative stress in IECs, leading to increased DNMT1 expression and activity 23,46) . The proinflammatory cytokine Interluekin-1β (IL-1β), secreted from immune cells within the lamina propria, also stimulates DNMT1 activity in a nitric oxide (NO)-dependent manner through upregulation of inducible nitric oxide synthase (iNOS) in IECs ( Fig.…”

Section: Microbiota-mediated Epigenetic Regulation Of Intestinal Epitmentioning

confidence: 99%

See 2 more Smart Citations

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Takahashi

Hase

2015

Inflammation and Regeneration

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Commensal microbiota colonizing the digestive tract is a symbiotic partner of its host, as it plays a critical role in nutrient metabolism as well as the development and maturation of the host immune system. Although it is clear that regulation of the host-commensal relationship is crucial to mammalian health, the underlying mechanisms regulating gut homeostasis are yet to be elucidated. Epigenetic modifications, including DNA methylation and histone methylation/acetylation, alter the structure of chromatin to regulate the transcriptional program of eukaryotic cells. At the whole genome level, these modifications possibly play a key role in regulating the mutually beneficial relationship between the host and the gut microbiota. In this review, we describe how the commensal microbiota and its metabolic by-products modify the epigenome of host cells, and in turn, change their development and functional behavior.Rec.2/24/2015, Acc.3/1/2015, pp129-136

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Section: Microbiota-mediated Epigenetic Regulation Of Intestinal Epitmentioning

confidence: 99%

Section: Microbiota-mediated Epigenetic Regulation Of Intestinal Epitmentioning

confidence: 99%

Section: Microbiota-mediated Epigenetic Regulation Of Intestinal Epitmentioning

confidence: 99%

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Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Takahashi

Hase

2015

Inflammation and Regeneration

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“…Alterations to chromatin are central to the reprogramming of pathological gene expression, which is directly relevant to many inflammatory diseases, including IBD (2,13,14). Studies have shown that DNA methylation is well correlated with various aspects of IBD, including disease duration and severity of inflammation (15,16).…”

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confidence: 99%

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Liu

Peng

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Epithelial barrier disruption is a major cause of inflammatory bowel disease (IBD); however, the mechanism through which epigenetic regulation modulates intestinal epithelial integrity remains largely undefined. Here we show that EZH2, the catalytic subunit of polycomb repressive complex (PRC2), is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. In accordance with reduced EZH2 expression in patients, the inactivation of EZH2 in IECs sensitizes mice to DSS-and TNBSinduced experimental colitis. Conversely, EZH2 overexpression in the intestinal epithelium renders mice more resistant to colitis. Mechanistically, the genes encoding TRAF2/5 are held in a finely tuned bivalent status under inflammatory conditions. EZH2 deficiency potentiates the expression of these genes to enhance TNFα-induced NF-κB signaling, thereby leading to uncontrolled inflammation. More importantly, we show that EZH2 depletion compromises the protective role of NF-κB signaling in cell survival by directly up-regulating ITCH, a well-known E3 ligase that degrades the c-FLIP protein. Thus, our findings highlight an epigenetic mechanism by which EZH2 integrates the multifaceted effects of TNFα signaling to promote the inflammatory response and apoptosis in colitis.colitis | EZH2 | TNFα | NF-κB | ITCH

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“…Inflammatory bowel disease has complex pathogenesis involving genetic susceptibility, intestinal microbiota, the host immune system and environmental factors such as diet, stress, smoking and hygiene (26). Defects in signalling pathways can lead to dysregulation of the inflammatory response that are crucial in the pathogenesis of IBD.…”

Section: Discussionmentioning

confidence: 99%

Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients

Παπουτσοπουλου

Burkitt

Bergey

et al. 2019

Preprint

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The heterogeneous nature of inflammatory bowel disease (IBD) presents challenges, particularly when choosing therapy. Activation of the NF-B transcription factor is a highly-regulated, dynamic event in IBD pathogenesis. We expressed the human NF-B/p65 subunit in blood-derived macrophages, using lentivirus. Confocal imaging of p65 activation revealed that a higher proportion of macrophages from Crohn's patients responded to lipid-A compared to controls. In contrast, cells from ulcerative colitis (UC) patients exhibited a shorter duration of p65 nuclear localisation compared to healthy controls and Crohn's donors. Using a similar lentivirus approach, NF-B-regulated luciferase was expressed in patient macrophages, isolated from frozen peripheral blood mononuclear cell samples. Following activation, samples could be segregated into three clusters based on the NF-B-regulated luciferase response. The majority of UC samples appeared in hypo-responsive cluster 1, with Crohn's patients representing the majority of hyper-responsive cluster 3. A positive correlation was seen between NF-B-induced luciferase activity and cytokine levels released to medium from stimulated macrophages, but not in serum or biopsy. Analysis of macrophage cytokine responses and patient metadata revealed a strong correlation between Crohn's patients who smoked and hyperactivation of p65. These in vitro dynamic assays of NF-B activation in blood-derived macrophages segregate IBD patients into groups with different phenotypes and therefore may help determine response to therapy.

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Linking Immunity, Epigenetics, and Cancer in Inflammatory Bowel Disease

Cited by 42 publications

References 225 publications

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Commensal microbiota-derived signals regulate host immune system through epigenetic modifications

Epithelial EZH2 serves as an epigenetic determinant in experimental colitis by inhibiting TNFα-mediated inflammation and apoptosis

Macrophage-specific NF-κB activation dynamics can segregate inflammatory bowel disease patients

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