Inflammatory Bowel Disease and Adenomas in Mice Expressing a Dominant Negative N-Cadherin

Hermiston, Michelle L.; Gordon, Jeffrey I.

doi:10.1126/science.270.5239.1203

Cited by 609 publications

(366 citation statements)

References 29 publications

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“…Transgenic IBD models that retain a complete repertoire of immune effectors have clearly demonstrated the relative importance that loss of epithelial integrity plays in driving subsequent abnormal mucosal inflammation and neoplasia. In mice expressing a dominant negative N-cadherin mutant under control of the intestinal epithelial-specific gene promoter for fatty acid binding protein, an IBD showing similarities to Crohn's disease is initiated via the disruption of intestinal epithelial adhesion (Hermiston and Gordon, 1995).…”

Section: Pathophysiology Of Enteric Glial Cells In Relation To Inflammentioning

confidence: 99%

Role of enteric glial cells in inflammatory bowel disease

Cabarrocas

Savidge

Liblau

2002

Glia

160

154

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Enteric glial cells (EGCs) represent an extensive but relatively poorly described cell population within the gastrointestinal tract. Accumulating data suggest that EGCs represent the morphological and functional equivalent of CNS astrocytes within the enteric nervous system (ENS). The EGC network has trophic and protective functions toward enteric neurons and is fully implicated in the integration and the modulation of neuronal activities. Moreover, EGCs seem to be active elements of the ENS during intestinal inflammatory and immune responses, sharing with astrocytes the ability to act as antigen-presenting cells and interacting with the mucosal immune system via the expression of cytokines and cytokine receptors. Transgenic mouse systems have demonstrated that specific ablation of EGC by chemical ablation or autoimmune T-cell targeting induces an intestinal pathology that shows similarities to the early intestinal immunopathology of Crohn's disease. EGCs may also share with astrocytes the ability to regulate tissue integrity, thereby postulating that similar interactions to those observed for the blood-brain barrier may also be partly responsible for regulating mucosal and vascular permeability in the gastrointestinal tract. Disruption of the EGC network in Crohn's disease patients may represent one possible cause for the enhanced mucosal permeability state and vascular dysfunction that are thought to favor mucosal inflammation. GLIA 41:81-93, 2003.

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Section: Pathophysiology Of Enteric Glial Cells In Relation To Inflammentioning

confidence: 99%

Role of enteric glial cells in inflammatory bowel disease

Cabarrocas

Savidge

Liblau

2002

Glia

160

154

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“…When these mice become mature their intestinal epithelium is a mosaic of normal epithelium and leaky epithelium, where the N-cadherin prevents E-cadherin from signalling to the cell to maintain polarity. In those areas of leaky gut, a chronic inflammatory bowel disease develops [7]. Along the same lines, Viney and colleagues have studied a mouse strain in whom the multi drug resistance 1a gene is disrupted.…”

Section: Mouse Models Have Told Us That T-cell Responses To the Residmentioning

confidence: 99%

Recent Developments in the Immunology of Inflammatory Bowel Disease

2000

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Crohn's disease and ulcerative colitis are caused by excessive immune reactivity in the gut wall. Analysis of the type of immune responses ongoing in diseased gut has revealed important features which suggest that these conditions are different. In Crohn's disease tissue there is considerable evidence for an ongoing T helper cell type 1 response, with excess interleukin‐12, interferon‐γ and TNF‐α. There is circumstantial evidence in patients that this response is directed against the normal bacterial flora and definitive evidence in mouse models that T cell responses to the flora cause gut disease. In ulcerative colitis, the role of tissue damaging T cell responses in the gut mucosa is much less clear and there is more evidence that the lesion is owing to antibody‐mediated hypersensitivity. Although different types of immune reactions initiate tissue injury in both Crohn's disease and ulcerative colitis, the downstream events which actually damage the tissue are the same in each condition. Elevated cytokine concentrations in the mucosa lead to the production of excess matrix degrading enzymes by gut fibroblasts, loss of mucosal integrity and ulceration. The same process also leads to an increased production of epithelial growth factors such as KGF Keratinocyte Growth Factor by gut fibroblasts and produces the crypt cell hyperplasia characteristic of all gut inflammatory conditions.

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“…Original magnification, ×63 (A); ×20 (B). ment significant downregulation of endogenous E-cadherin (24,47). DN-cadherin expression has, in fact, been used extensively to disrupt cell-cell adhesion in cultured cells and in vivo.…”

Section: Figurementioning

confidence: 99%

“…In particular, transgenic expression of a dominant-negative cadherin (DN-cadherin) in the mouse small intestine induces a Crohn-like IBD by 3 months of age, and the majority of these animals develop adenomas within 6 months (24). IBDs (e.g., Crohn disease, ulcerative colitis) are chronically remitting inflammatory conditions, affecting over 1.4 million Americans (25).…”

Section: Introductionmentioning

confidence: 99%

p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

Smalley-Freed¹,

Ефимов²,

Burnett³

et al. 2010

J. Clin. Invest.

125

152

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Epithelial-cadherin (E-cadherin) is a master organizer of the epithelial phenotype. Its function is regulated in part by p120-catenin (referred to herein as p120), a cytoplasmic binding partner that directly regulates cadherin stability. As it has been suggested that cadherins have a role in inflammatory bowel disease (IBD), we sought to investigate this further by assessing the effect of p120 deficiency in mouse small intestine and colon. p120 conditional KO mice were superficially normal at birth but declined rapidly and died within 21 days. Cellcell adhesion defects and inflammation led to progressive mucosal erosion and terminal bleeding, similar to what is observed in a dominant-negative cadherin mouse model of IBD. Additionally, selective loss of adherens junctions and accumulation of atypical COX-2-expressing neutrophils in p120-null areas of the colon were observed. To elucidate the mechanism, direct effects of p120 deficiency were assessed in vitro in a polarizing colon cancer cell line. Notably, transepithelial electrical resistance was dramatically reduced, neutrophil binding was increased 30 fold, and levels of COX-2, an enzyme associated with IBD, were markedly increased in neutrophils. Our data suggest that p120 loss disrupts the neonatal intestinal barrier and amplifies neutrophil engagement and that these changes lead to catastrophic inflammation during colonization of the neonatal gut with bacteria and other luminal antigens. Thus, we conclude that p120 has an essential role in barrier function and epithelial homeostasis and survival in the intestine.

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Inflammatory Bowel Disease and Adenomas in Mice Expressing a Dominant Negative N-Cadherin

Cited by 609 publications

References 29 publications

Role of enteric glial cells in inflammatory bowel disease

Role of enteric glial cells in inflammatory bowel disease

Recent Developments in the Immunology of Inflammatory Bowel Disease

p120-catenin is essential for maintenance of barrier function and intestinal homeostasis in mice

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