Epithelial: Lamina Propria Lymphocyte Interactions Promote Epithelial Cell Differentiation

SummarySince their discovery more than 15 years ago, the mitogen activated protein kinases (MAPK) have been implicated in an ever-increasingly diverse array of pathways, including inflammatory signalling cascades. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by the perpetual production of inflammatory mediators. Research into the transduction pathway behind this over-production has highlighted the potential mediating role for the MAPKs and their related signalling components. This review highlights some of the research into the role for the MAPKs and their related signalling proteins in influencing the progression of IBD.

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“…Similarly, increased phosphorylation of JNK1/2 was seen in inflamed tissue from IBD patients [29,52,53].…”

Section: The Jnk Mapkmentioning

confidence: 80%

Mitogen activated protein kinases: a role in inflammatory bowel disease?

Broom

Widjaya

Troelsen

et al. 2009

Clinical and Experimental Immunology

160

114

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“…PI3K activity has been shown to be required for TNF␣-and IL-13-induced claudin-2 expression (15,33). The colonic epithelium of active Crohn disease and ulcerative colitis patients also exhibits higher pERK and pAkt activity, suggesting that activated signaling pathways might be associated with the dysregulation of epithelial function in IBD (38). Our results demonstrated that increased phosphorylation of ERK and Akt is required for the IL-6-mediated claudin-2 expression leading to cation-selective TJ permeability.…”

Section: Discussionmentioning

confidence: 99%

“…(n ϭ 4). plays a critical role in both the transcriptional regulation of intestinal genes, including claudin-2, and the differentiation of intestinal epithelial cells (38). Cdx2 expression is localized only in the epithelial cells at the luminal surface in normal colons, while it occurs also in the colonic crypt in Crohn disease and ulcerative colitis patients (38).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Suzuki

Yoshinaga

Tanabe

2011

Journal of Biological Chemistry

451

366

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In inflammatory bowel diseases (IBD), intestinal barrier function is impaired as a result of deteriorations in epithelial tight junction (TJ) structure. IL-6, a pleiotropic cytokine, is elevated in IBD patients, although the role of IL-6 in barrier function remains unknown. We present evidence that IL-6 increases TJ permeability by stimulating the expression of channel-forming claudin-2, which is required for increased caudal-related homeobox (Cdx) 2 through the MEK/ERK and PI3K pathways in intestinal epithelial cells. IL-6 increases the cation-selective TJ permeability without any changes to uncharged dextran flux or cell viability in Caco-2 cells. IL-6 markedly induces claudin-2 expression, which is associated with increased TJ permeability. The colonic mucosa of mice injected with IL-6 also exhibits an increase in claudin-2 expression. The claudin-2 expression and TJ permeability induced by IL-6 are sensitive to the inhibition of gp130, MEK, and PI3K. Furthermore, expression of WT-MEK1 induces claudin-2 expression in Caco-2 cells. Claudin-2 promoter activity is increased by IL-6 in a MEK/ERK and PI3K-dependent manner, and deletion of Cdx binding sites in the promoter sequence results in a loss of IL-6-induced promoter activity. IL-6 increases Cdx2 protein expression, which is suppressed by the inhibition of MEK and PI3K. These observations may reveal an important mechanism by which IL-6 can undermine the integrity of the intestinal barrier.

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“…The activation of MAPK-ERK1/2 phosphorylates the downstream proinflammatory proteins such as cytosolic phospholipase A2 and some transcription factors such as activated proteins, Ets-1, Elk and c-myc. Interestingly, ERK1/2, by a study using an ERK1/2 inhibitor, was found to play an important role in the function of immune cells and other cell types during IBD, by regulating some pro-inflammatory mediators [such as interleukin-1 (IL-1)] related signaling transduction [81,82] , evidenced by their enhanced expression and phosphorylation status during IBD [83,84] . Furthermore, the "tightening" junction protein claudin-4, which plays an important role in epithelial barrier function, is regulated by protein kinase ERK [85] .…”

Section: Of Ibdmentioning

confidence: 99%

“…By inducing Akt but blocking p38 signaling, Lactobacillus GG prevents cytokine-induced apoptosis of intestinal epithelial cells, indicating p38 and Akt as key mediators of epithelial barrier function [86,87] . p38 activity is increased significantly in tissues from IBD patients and in mouse models of colitis [83,84,88] , in which inhibition of p38 lowers KC (IL-8) and IL-6 production. A similar result was reported that heatkilled Lactobacillus brevis phosphorylates p38 kinase to regulate the expression of proinflammatory cytokines such as TNF-α, and to improve intestinal integrity [89] .…”

Section: Of Ibdmentioning

confidence: 99%

Protein kinases are potential targets to treat inflammatory bowel disease

Yang

Yan

2014

WJGPT

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Protein kinases play a crucial role in the pathogenesis of inflammatory bowel disease (IBD), the two main forms of which are ulcerative colitis and Crohn's disease. In this article, we will review the mechanisms of involvement of protein kinases in the pathogenesis of and intervention against IBD, in terms of their effects on genetics, microbiota, mucous layer and tight junction, and the potential of protein kinases as therapeutic targets against IBD.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Inflammatory bowel disease; Protein kinase; Barrier function; Microbiota; Genetics Core tip: The roles of protein kinases in the pathogenesis and intervention of inflammatory bowel diseases (IBD) are emerging. In this article, we will review the specific roles of different protein kinases in the pathogenesis of IBD, classify these protein kinases into different categories based on their fundamental functions in IBD, and describe substantial new mechanistic insights into the pathogenesis of IBD, highlighting protein kinases as potential intervention targets against IBD.

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Epithelial: Lamina Propria Lymphocyte Interactions Promote Epithelial Cell Differentiation

Cited by 69 publications

References 34 publications

Mitogen activated protein kinases: a role in inflammatory bowel disease?

Mitogen activated protein kinases: a role in inflammatory bowel disease?

Interleukin-6 (IL-6) Regulates Claudin-2 Expression and Tight Junction Permeability in Intestinal Epithelium

Protein kinases are potential targets to treat inflammatory bowel disease

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