Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021390 (inflammatory bowel disease)
 23,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The efficient repair of gastrointestinal mucosal injuries is essential in the preservation of the epithelial barrier to luminal antigens. Accumulated evidence suggests that epithelial migration plays a major part in this repair by rapidly resealing defects induced by both physiological and pathological insults, a process termed restitution. 2. This migration has been modelled in various ways, most commonly in mechanically wounded monolayers of cell lines or cells in primary culture, and in wounded human or animal tissue. Evidence from these models indicates that migration is a highly complex process, which is likely to involve the tightly controlled spatial and temporal interaction of multiple factors: (i) extracellular molecules such as soluble factors (e.g. growth factors, trefoil peptides, cytokines) and matrix components (e.g. collagen, laminin, fibronectin); (ii) signalling molecules activated by the interaction of these factors with cell surface receptors (e.g. protein kinases, phospholipases, low-molecular-weight GTPases); (iii) factors which regulate adhesion to other cells (e.g. E-cadherin) and to matrix components (e.g. integrins, hyaluronic acid receptors); (iv) factors which regulate detachment from the extracellular matrix (e.g. urokinase-type plasminogen activator, matrix metalloproteinases); and (v) molecules which regulate cytoskeletal function (e.g. Rac), which allows the formation of specialized cellular processes termed lamellipodia. 3. The identification of physiologically relevant factors that stimulate epithelial cell migration, and a better understanding of their mechanism of action, may be beneficial in the development of novel therapeutic approaches in diseases such as inflammatory bowel disease through the pharmacological or dietary enhancement of this migration.
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PMID:Epithelial migration in the colon: filling in the gaps. 930 23

Catenins are cytoplasmic proteins associated with E-cadherin, the prime mediator of cell-cell adhesion. Perturbation in any of these molecules results in altered intercellular adhesion, cell differentiation, and increased migration. In this study, the expression and cellular localization of catenins and E-cadherin in inflammatory bowel disease were examined. The expression of E-cadherin; alpha-, beta-, and gamma-catenin; and p120 was evaluated immunohistochemically in 31 paraffin-embedded colonic specimens from 21 patients with ulcerative colitis and Crohn's disease. Loss of normal membranous E-cadherin and alpha-catenin staining was detected at the mucosal edges around epithelial ulcerations in all cases of active ulcerative colitis and in 50 per cent of cases with active Crohn's disease. Reduced expression of p120 protein was also found at the margins of ulcerated mucosa in all cases of active ulcerative colitis and in 75 per cent of those with active Crohn's disease. There was a statistically significant correlation between the expression of E-cadherin, alpha-catenin and p120 and disease activity. There were no changes in beta- and gamma-catenin expression in either ulcerative colitis on Crohn's disease. These findings indicate that altered expression of E-cadherin, alpha-catenin, and p120 occurs during mucosal ulceration in inflammatory bowel disease. These changes may be involved in promoting cell migration during epithelial restitution of the gastrointestinal mucosa.
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PMID:Expression of catenins and E-cadherin during epithelial restitution in inflammatory bowel disease. 982 41

The recognition of key roles for cadherins in the determination of epithelial cell phenotype, migration, differentiation, and tumour dissemination have stimulated much interest in this family of adhesion molecules. In the gastrointestinal tract, alteration of the expression of classical cadherins with aberrant P-cadherin up-regulation, associated with co-expression or loss of E-cadherin expression, is seen in neoplastic transformation of oral and oesophageal squamous mucosa and in lesions representing early neoplastic transformation of glandular mucosa, such as aberrant crypt foci and metaplastic and adenomatous polyps. This same phenotype is seen in enterocytes adjacent to foci of ulceration in the intestine in colitis, including inflammatory bowel disease, and in colitis-associated dysplasia. In coeliac disease, reversible E-cadherin down-regulation correlates with the degree of villous atrophy, but in contrast with colitis, aberrant P-cadherin expression is not a feature. Aberrant epithelial P-cadherin expression is thus associated with a proliferative phenotype related to ulceration and neoplastic transformation in the gastrointestinal tract, which may confer a survival advantage on these cells, but the relative functional roles of P-cadherin and E-cadherin and the molecular mechanisms underlyingP-cadherin/catenin interactions have yet to be elucidated.
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PMID:Aberrant P-cadherin expression is a feature of clonal expansion in the gastrointestinal tract associated with repair and neoplasia. 1072 77

Changes of the intestinal mucosal barrier are considered to play a role in the pathogenesis of inflammatory bowel disease (IBD). Our experiments were designed to identify dysregulation of epithelial junctional molecules in the IBD intestinum and to address whether altered expression of these molecules is a primary event in IBD or a phenomenon secondary to the inflammatory process. Noninflamed and inactively and actively inflamed mucosal tissues from patients with ulcerative colitis or Crohn's disease as well as tissues from control subjects were analyzed for the expression of junctional molecules by different methods. Marked downregulation of junctional proteins and their respective mRNAs was observed in actively inflamed IBD tissues. In IBD tissues with inactive inflammation, only a few junctional molecules such as E-cadherin and alpha-catenin were affected, whereas expression of desmosomal or tight junction-associated proteins appeared almost unchanged. In noninflamed IBD tissues, junctional protein expression was not different from that seen in normal control subjects. In IBD, downregulation of junctional molecule expression is apparently associated with the inflammatory process and does not likely represent a primary phenomenon.
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PMID:Inflammatory bowel disease is associated with changes of enterocytic junctions. 1140 75

Inflammatory bowel disease (IBD) consisting of ulcerative colitis (UC) and Crohn's (CD) typically displays a waxing and waning course punctuated by disease flares that are characterized by transepithelial migration of neutrophils (PMN) and altered barrier function. Since epithelial barrier function is primarily regulated by the apical most intercellular junction referred to as the tight junction (TJ), our aim was to examine expression of TJ and adherens junction (AJ) proteins in relation to PMN infiltration in mucosal tissue samples from patients with active IBD. Expression of epithelial intercellular TJ proteins (occludin, ZO-1, claudin-1, and JAM) and subjacent AJ (beta-catenin and E-cadherin) proteins were examined by immunoflourescence/confocal microscopy, immunohistochemistry, and Western blotting. Colonic mucosa from patients with UC revealed dramatic, global down-regulation of the key TJ transmembrane protein occludin in regions of actively transmigrating PMN and in quiescent areas in the biopsy samples. Significant decreases in occludin expression were observed at the protein and mRNA levels by Western and Northern blotting. In contrast, expression of other TJ and AJ proteins such as ZO-1, claudin-1, JAM, beta-catenin, and E-cadherin were down-regulated only in epithelial cells immediately adjacent to transmigrating PMN. Analysis of inflamed mucosa from Crohn's disease patients mirrored the results obtained with UC patients. No change in TJ and AJ protein expression was observed in colonic epithelium from patients with collagenous colitis or lymphocytic colitis that are respectively characterized by a thickened subepithelial collagen plate and increased intraepithelial lymphocytes. These results suggest that occludin expression is diminished in IBD by mechanisms distinct from those regulating expression of other intercellular junction proteins. We speculate that down-regulation of epithelial occludin may play a role in enhanced paracellular permeability and PMN transmigration that is observed in active inflammatory bowel disease.
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PMID:Neutrophil transmigration in inflammatory bowel disease is associated with differential expression of epithelial intercellular junction proteins. 1173 50

Intraepithelial lymphocytes play an important role in mucosal immunology, and are involved in the pathogenesis of inflammatory bowel disease. We studied expression of CD103 on mucosal lymphocytes with epithelial adhesion molecules in patients with inflammatory bowel disease. Surgical specimens of human colon were obtained from 12 patients with ulcerative colitis, 12 patients with Crohn's disease, and 5 controls. Frozen sections were cut and expression of CD103 on lymphocytes, E-cadherin, CD44V3, and CD44v6 on intestinal epithelium was studied. Frequency of CD103-positive intraepithelial lymphocytes did not differ among controls, patients with ulcerative colitis, and patients with Crohn's disease. The frequency of CD103-positive lamina propria lymphocytes was significantly higher in patients with Crohn's disease than in controls and patients with ulcerative colitis. The frequency of CD103-positive intraepithelial lymphocytes was significantly correlated with that of lamina propria lymphocytes in patients with ulcerative colitis. The frequency of CD103-positive intraepithelial lymphocytes was significantly correlated with epithelial E-cadherin expression but that of lamina propria lymphocytes was not. Differential up-regulation of CD103 expression on lamina propria lymphocytes in Crohn's disease may indicate differential humoral or cellular regulation in inducing CD103 molecules on lymphocytes in patients with this disease.
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PMID:Differential expression of homing receptor CD103 on lamina propria lymphocytes and association of CD103 with epithelial adhesion molecules in inflammatory bowel disease. 1453 99

Colon carcinoma arising in inflammatory bowel disease often exhibits aggressive behavior compared to sporadic carcinomas. The rationale for the different biological behaviors of these two groups of tumors is not fully understood. In this study, we have examined carcinomas arising in inflammatory bowel disease (IBD) and sporadic carcinomas (SCA) for molecular differences that may provide clues for the behavioral disparity of these tumors. Thirty-eight colon carcinomas (12 from ulcerative colitis, 5 from Crohn's disease, and 21 SCA) were analyzed by immunohistochemistry for cell adhesion molecules (E-cadherin, beta-catenin, CD44), cell cycle regulatory proteins (cyclin D1, p27, p21), mismatch repair proteins (hMLH1, hMSH2), cyclooxygenase-2 and DPC4. Carcinomas arising in IBD showed significant decrease in expression of cell adhesion molecules, the cell cycle inhibitor protein, p21, and increased expression of cyclooxygenase-2 compared to sporadic carcinomas. No differences were observed in the expression of cell cycle regulatory proteins p27, cyclin D1, DPC4 and mismatch repair proteins between these two groups of tumors. Decreased expression of p21 as well as adhesion molecules may provide increased impetus for the aggressive behavior of tumors arising in inflammatory bowel disease.
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PMID:Comparative analysis of cell adhesion molecules, cell cycle regulatory proteins, mismatch repair genes, cyclooxygenase-2, and DPC4 in carcinomas arising in inflammatory bowel disease and sporadic colon cancer. 1506 31

The intestinal epithelium is characterized by rapid cellular turnover with continuous proliferation of multipotential stem cells within Lieberkuhn's crypts, cellular migration along the crypt-villus axis, cellular differentiation, polarization, apical apoptosis, and luminal shedding. These processes are critical for the development and maintenance of normal intestinal epithelial architecture and function and involve complex cell-cell and cell-substratum interactions, which are mediated by epithelial (E)-cadherin and the integrins, respectively. This review outlines the role of E-cadherin and its cytoplasmic binding proteins, the catenins, as well as the interplay with other mucosal adhesion and restitution molecules during physiological processes in the intestinal epithelium mediating embryogenesis, cellular differentiation, cellular migration, and mucosal repair, as well as what is known about the dysregulation of assembly of the E-cadherin-catenin adhesion complex in inflammatory bowel disease.
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PMID:Cadherins: an integral role in inflammatory bowel disease and mucosal restitution. 1517 38

Anoikis, i.e. apoptosis induced by detachment from the extracellular matrix, is thought to be involved in the shedding of enterocytes at the tip of intestinal villi. Mechanisms controlling enterocyte survival are poorly understood. We investigated the role of E-cadherin, a key protein of cell-cell adhesion, in the control of anoikis of normal intestinal epithelial cells, by detaching murine villus epithelial cells from the underlying basement membrane while preserving cell-cell interactions. We show that upon the loss of anchorage, normal enterocytes execute a program of apoptosis within minutes, via a Bcl-2-regulated and caspase-9-dependent pathway. E-cadherin is lost early from cell-cell contacts. This process precedes the execution phase of detachment-induced apoptosis as it is only weakly modulated by Bcl-2 overexpression or caspase inhibition. E-cadherin loss, however, is efficiently prevented by lysosome and proteasome inhibitors. We also found that a blocking anti-E-cadherin antibody increases the rate of anoikis, whereas the activation of E-cadherin using E-cadherin-Fc chimera proteins reduces anoikis. In conclusion, our results stress the striking sensitivity of normal enterocytes to the loss of anchorage and the contribution of E-cadherin to the control of their survival/apoptosis balance. They open new perspectives on the key role of this protein, which is dysregulated in the intestinal epithelium in both inflammatory bowel disease and cancer.
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PMID:Early loss of E-cadherin from cell-cell contacts is involved in the onset of Anoikis in enterocytes. 1529 48

A key feature of inflammatory bowel disease (IBD) is disruption of the intestinal epithelial barrier by unknown mechanisms. Integrity of the epithelial barrier is determined by an apical junctional complex that is composed of tight junction (TJ) and adherens junction (AJ). Previous observations have suggested that alterations in the apical junctional complex occur in IBD. Localization studies in mucosal biopsies from IBD patients have revealed disappearance of key TJ (occludin, JAM1, ZO1, claudin 1) and AJ (E-cadherin, beta-catenin) proteins from intercellular junctions. In vitro experiments examining the effects of inflammatory cytokines on model intestinal epithelial monolayers suggest that disruption of the epithelial barrier is associated with internalization of transmembrane TJ proteins, JAM1, ocdudin and claudins 1/4. The mechanism(s) of internalization of intercellular junctions can be modelled in vitro by calcium depletion of confluent epithelial cell monolayers. Using this model, we have observed rapid, orchestrated endocytosis of all AJ and TJ proteins into a subapical cytoplasmic compartment that is independent of caveolae/lipid rafts and macropinocytosis. However, inhibitors of clathrin-mediated endocytosis effectively block internalization of AJs and TJs, and junctional proteins colocalize with clathrin. Interestingly, internalized AJ and TJ proteins enter early endosomes followed by movement to organelles that do not label with markers of late and recycling endosomes, lysosomes or Golgi but appear to represent a unique storage compartment that colocalizes with t-SNARE protein, syntaxin 4. A better understanding of the mechanisms of junctional internalization and recycling will likely provide new insights into the mechanisms of altered barrier function in IBD.
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PMID:The epithelium in inflammatory bowel disease: potential role of endocytosis of junctional proteins in barrier disruption. 1566 38


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