Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B0FTZ7 (catenin)
 18,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelial cell (EC) junctions regulate circulating leukocyte extravasation and infiltration at inflammatory sites. Several lines of evidence show that platelet endothelial cell adhesion molecule-1 (PECAM-1), a specific component of EC junctions, is required for leukocyte transmigration through EC monolayers. In this paper, we examined the effects of two inflammatory cytokines, TNF-alpha and IFN-gamma, on PECAM-1 and vascular endothelial-cadherin/catenin organization. We found that the addition of inflammatory cytokines (TNF-alpha plus IFN-gamma in combination, for > or = 24 h) caused PECAM-1 to disappear from EC intercellular contacts. Confocal microscopy indicated that after treatment with the cytokines, PECAM-1 was rapidly internalized. In addition, a strong inhibition of PECAM-1 synthesis and a decrease in PECAM-1 mRNA were observed. This phenomenon was only found when TNF-alpha plus IFN-gamma were used in combination. Adhesion of polymorphonuclear cells to doubly treated EC was increased compared with control cells or cells incubated with TNF-alpha or IFN-gamma separately. This was correlated with an increased expression of intercellular adhesion molecule-1. However, the disappearance of PECAM-1 from cell junctions after treatment with TNF-alpha plus IFN-gamma was accompanied by a marked reduction of leukocyte migration through EC monolayers. The correlation between PECAM-1 level and leukocyte transmigration was supported by transmigration inhibition assays using blocking anti-PECAM-1 mAb. These data indicate that PECAM-1 is a specific target of inflammatory cytokines and suggest that changes in its synthesis and organization might negatively modulate leukocyte recruitment.
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PMID:Inhibition of platelet endothelial cell adhesion molecule-1 synthesis and leukocyte transmigration in endothelial cells by the combined action of TNF-alpha and IFN-gamma. 875 31

Celiac disease is characterized by a chronic immune response to dietary gluten, in which T cell responses result in elevated mucosal levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, interferon (IFN)-gamma, and transforming growth factor (TGF)-beta, which induce profound mucosal remodeling associated with increased enterocyte proliferation, apoptosis, and migration. Reduced intestinal expression of the morphoregulatory cell adhesion molecule E-cadherin, which forms complexes with beta-catenin, can increase enterocyte proliferation and migration. However, its mechanism of action in gastrointestinal inflammatory conditions and any involvement in celiac disease is unknown. In this study, we describe changes in E-cadherin and beta-catenin expression in celiac disease tissue and determine the effect of cytokines on their expression in an in vitro model. We assessed E-cadherin and beta-catenin expression in intestinal biopsies from 24 patients with celiac disease, 12 patients with treated celiac disease, and 10 healthy patients by immunohistochemistry, Western blotting, and confocal microscopy. Using Caco-2 cells, we examined the effect of TNF-alpha, IL-1, IFN-gamma, and TGF-beta on E-cadherin expression. E-cadherin transcription was assessed in both intestinal biopsies and Caco-2 cells by in situ hybridization and RT-PCR, respectively. A marked reduction in protein expression of E-cadherin and beta-catenin that returns to normal levels after treatment was observed in celiac disease; this reduction was associated with reduced levels of E-cadherin mRNA. E-cadherin expression in Caco-2 cells was significantly reduced after TNF-alpha, IL-1, and IFN-gamma stimulation. The effect of TNF-alpha on E-cadherin expression was maximal after stimulation for 48 hours and also induced modest reductions in beta-catenin expression. The action of TNF-alpha on E-cadherin was reversible and was shown to act at the transcriptional level. These results demonstrate the novel findings that E-cadherin and beta-catenin expression are reversibly down-regulated in celiac disease and that such changes in epithelial cadherin/catenin complexes may be mediated by cytokines acting on cadherin transcription.
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PMID:Reduced cadherin/catenin complex expression in celiac disease can be reproduced in vitro by cytokine stimulation. 1061