Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a(−/−) mice

Collett, Andrew; Higgs, N B; Gironella, Meritxell; Zeef, Leo; Hayes, Andrew; Salmo, Emil; Haboubi, Najib; Iovanna, Juan; Carlson, Gordon L; Warhurst, Geoffrey

doi:10.1002/ibd.20375

Cited by 46 publications

(36 citation statements)

References 49 publications

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“…We now demonstrate that prophylaxis with this TLR2 ligand prevents spontaneous onset of chronic colitis. Pathogenesis of commensaldriven pancolitis in FVB/N mice deficient in MDR1␣ gene expression involves primary IEC barrier dysfunction associated with alterations in interferon ␥-responsive genes in the lamina propria (43)(44)(45)(46). Despite presence of CC-chemokines and proinflammatory interferon ␥ in the mucosal milieu, which disrupt Cx43 (11,58), treatment with PCSK suppressed inflammatory induced accumulation, Ser 368 phosphorylation, and morphological disruption of Cx43 in intestinal epithelial cells in parallel with delayed onset of mucosal disease.…”

Section: Discussionmentioning

confidence: 99%

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury

Eyking

Gerken

et al. 2009

Journal of Biological Chemistry

105

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Gap junctional intercellular communication (GJIC) coordinates cellular functions essential for sustaining tissue homeostasis; yet its regulation in the intestine is not well understood. Here, we identify a novel physiological link between Toll-like receptor (TLR) 2 and GJIC through modulation of Connexin-43 (Cx43) during acute and chronic inflammatory injury of the intestinal epithelial cell (IEC) barrier. Data from in vitro studies reveal that TLR2 activation modulates Cx43 synthesis and increases GJIC via Cx43 during IEC injury. The ulcerative colitis-associated TLR2-R753Q mutant targets Cx43 for increased proteasomal degradation, impairing TLR2-mediated GJIC during intestinal epithelial wounding. In vivo studies using mucosal RNA interference show that TLR2-mediated mucosal healing depends functionally on intestinal epithelial Cx43 during acute inflammatory stress-induced damage. Mice deficient in TLR2 exhibit IEC-specific alterations in Cx43, whereas administration of a TLR2 agonist protects GJIC by blocking accumulation of Cx43 and its hyperphosphorylation at Ser 368 to prevent spontaneous chronic colitis in MDR1␣-deficient mice. Finally, adding the TLR2 agonist to three-dimensional intestinal mucosalike cultures of human biopsies preserves intestinal epithelial Cx43 integrity and polarization ex vivo. In conclusion, Cx43 plays an important role in innate immune control of commensal-mediated intestinal epithelial wound repair.

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Section: Discussionmentioning

confidence: 99%

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury

Eyking

Gerken

et al. 2009

Journal of Biological Chemistry

105

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“…For both models of experimental colitis, it has been shown that levels of IFN-␥ are elevated (6,7). Colonic tissues from C57BL/6 mice subjected to acute DSS colitis showed a significant increase in EGFr expression compared with tissues from control C57/BL6 mice (Fig.…”

Section: Experimental Colitis Induces Opposing Effects On Egfrmentioning

confidence: 91%

“…Indeed, IFN-␥ Ϫ/Ϫ mice are resistant to DSS-induced colitis (5). In another model of spontaneous colitis, the mdr1a Ϫ/Ϫ mouse, IFN-␥ mRNA and protein levels are elevated more than 50-fold in mice with established colitis compared with controls, and production of IFN-␥ is also elevated in stimulated mesenteric lymph nodes (6,7). Interestingly, the human MDR gene is located on chromosome 7, a susceptibility locus for inflammatory bowel diseases (8).…”

mentioning

confidence: 99%

Interferon-γ Alters Downstream Signaling Originating from Epidermal Growth Factor Receptor in Intestinal Epithelial Cells

Paul

Marchelletta

McCole

et al. 2012

Journal of Biological Chemistry

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Background: Inflammation alters epithelial signaling. We studied how IFN-␥ regulates EGFr signaling. Results: IFN-␥ regulated EGFr expression, membrane localization, tyrosine residue phosphorylation, and linkage to MAPK. EGF no longer inhibited ion transport in IFN-␥-treated cells. Conclusion: EGFr signaling outcomes are altered by inflammation. Significance: These effects may contribute to diarrheal and other symptoms of inflammatory bowel diseases.

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“…However, it has been shown that MDR1 interferes with bacterial adhesion to enterocytes and reduces the risk of gastrointestinal disorders (15). Interestingly, at the same time, mdr1a-/-mice display reduced expression of regenerating islet-derived protein 3 gamma (REG3G) in intestinal mucosa (32). REG3G prevents exaggerated inflammation by bactericidal activity and suppression of cytokine production (33).…”

Section: Expression Of Cytokines and Socs Moleculesmentioning

confidence: 99%

Reduction of MDR1, MRP1 and BCRP expression in Crohn’s disease: a role in disease pathogenesis?

et al. 2015

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Background and purpose: ABC transporters have a non-redundant role in the maintenance of gut homeostasis and changes in their expressionIntroductIon C rohn's disease (CD) is a chronic intestinal bowel disorder (IBD) of unknown cause in which genetic and environmental factors, primarily microbial, influence the gastrointestinal tract's ability to balance pro-and anti-inflammatory mechanisms. The immunopathology is driven by innate cytokines like TNF-a, IL-6 and IL-1b that are responsible for the chemokine release and neutrophil infiltration. Their production is elevated in CD and they contribute to tissue damage directly or indirectly through elevation of matrix metalloproteinases (1-3). Presence of elevated expression and production of cytokines like IFN-g and IL-17, produced by CD4 Th1 and Th17 effector T cells, implicate an ongoing adaptive immune response in the CD (4, 5).

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Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a(−/−) mice

Abstract: These studies show that early epithelial changes associated with altered responsiveness to bacteria precede increased permeability and mucosal inflammation in this model of colitis, highlighting the importance of P-glycoprotein in regulating interactions with the commensal microflora.

Cited by 46 publications

References 49 publications

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury

TLR2 Mediates Gap Junctional Intercellular Communication through Connexin-43 in Intestinal Epithelial Barrier Injury

Interferon-γ Alters Downstream Signaling Originating from Epidermal Growth Factor Receptor in Intestinal Epithelial Cells

Reduction of MDR1, MRP1 and BCRP expression in Crohn’s disease: a role in disease pathogenesis?

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