Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
Int J Mol Med 2003 Nov
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

Dietary fat is an important factor involved in the pathogenesis of inflammatory bowel disease (IBD). It remains unclear how n-3 and n-6 fatty acids modulate intestinal inflammation. In this study, we investigated the effects of n-3 and n-6 fatty acid-rich diets on trinitrobenzene sulfonic acid (TNBS)-induced enteritis. The rats were fed an n-3 or n-6 rich-diet for 12 days, and then starved for the following 2 days. An intraileal injection of TNBS was administered, and TNBS-enteritis subsequently developed. Macroscopic and histological examination was performed after 24 h. Serum cytokine levels were determined by ELISA. The n-6 fatty acid-rich diet markedly enhanced mucosal damage as compared to the n-3 fatty acid-rich diet. The damage score was significantly higher in the n-6 fatty acid-rich diet group (P<0.05). Histological changes in the mucosa were more severe in the n-6 fatty acid-rich diet group than in the n-3 fatty acid-rich group. Serum IL-6 levels were significantly higher in the n-6 fatty acid-rich diet group than in the n-3 fatty acid-rich group (P<0.05). On the other hand, there were no differences in serum TNF-alpha levels. The n-3 fatty acid-rich diet effectively reduced early mucosal inflammation in TNBS enteritis. The effects of the n-3 fatty acids were associated with blockage of mucosal IL-6 secretion. Our data suggest that n-3 fatty acid-rich diet may be applicable for enteral nutrition in the treatment of IBD patients.
Int J Mol Med 2003 Nov
PMID:N-3 fatty acid-rich diet prevents early response of interleukin-6 elevation in trinitrobenzene sulfonic acid-induced enteritis. 1453

The human intestinal tract is constantly exposed to an enormous indigenous bacterial flora. It has recently been recognised that antimicrobial peptides of the defensin family likely play a role in protection against microbial invasion at a variety of mucosal epithelial surfaces, including that of the intestinal tract. To date, six alpha-defensins have been identified in humans. Four of these, designated Human Neutrophil Peptides (HNP) 1,2,3 and 4, form part of the armoury of neutrophils, where they participate in systemic innate immunity. The remaining two, Human Defensin (HD) 5 and 6, are expressed in intestinal Paneth cells, and probably contribute to innate defense of the GI mucosal surface. Murine intestinal alpha-defensins (the 'cryptdins') have been extensively studied, but less is known about their human counterparts. The putative mature HD-5 was chemically synthesised and used to raise polyclonal antiserum. Using this anti-HD-5 antiserum, the expression of HD-5 in normal and inflamed intestinal mucosal samples was studied using immunohistochemistry. HD-5 is expressed in Paneth cells and also in some villous epithelial cells in normal duodenum, jejunum and ileum. HD-5 is not expressed in the normal stomach or colon. In cases of gastritis, colonic Crohn's disease and ulcerative colitis, HD-5 is expressed in metaplastic Paneth cells. Utilizing the anti-HD-5 antiserum, native HD-5 was isolated and purified from acid extracts of normal terminal ileal mucosal epithelial cells using cation exchange and reverse phase high pressure liquid chromatography. The purified peptide was characterised using N-terminal amino acid sequence and mass spectral analysis. Antimicrobial activity of the peptide was assessed using a sensitive colony forming unit antimicrobial assay. HD-5 is stored in the predicted precursor form in Paneth cells, and this form does not have antimicrobial activity against a defensin sensitive Salmonella. Potential processing of the precursor form of the HD-5 peptide into a mature active form, was studied by stimulating Paneth cell granule secretion in freshly isolated, cultured ileal crypts. A truncated form of the precursor form of HD-5, but not the predicted mature form, was present in the culture supernatant. Recently published studies suggest that further processing of the molecule occurs in vivo. The expression of HNP 1-3 in the normal intestinal mucosa and in cases of inflammatory bowel disease was studied. In the normal intestinal mucosa, HNP are expressed only in sparse lamina propria neutrophils, and not in Paneth cells. In cases of active ulcerative colitis and Crohn's disease, scattered surface epithelial cells, as well as numerous lamina propria neutrophils, were seen to express HNP. In conclusion, HD-5 is stored only in its precursor form in normal ileal Paneth cells, and partial processing of the peptide to a mature form occurs during and/or after secretion. In inflammatory bowel disease, HD-5 is expressed in metaplastic Paneth cells in the colon, and HNP is expressed by some surface epithelial cells. These studies suggest that antimicrobial defensin peptides may be important in protection of the host against microbial invasion in states of intestinal inflammation.
Mol Immunol 2003 Nov
PMID:Alpha-defensins in the gastrointestinal tract. 1456 93

Current options to treat inflammatory bowel diseases (IBDs) are often associated with undesired side effects, have limited therapeutic benefit for many patients and do not lead to a complete restoration of the mucosal immune balance. Recent research progress in the pathogenesis of IBDs has widely broadened our understanding of the complex nature of these immunological disorders and identified new potential therapeutic targets. New insights into the molecular mechanisms underlying IBDs may now allow the development of new in vivo or ex vivo therapeutic gene treatment strategies that alter the biological functions of cells in the inflamed gastrointestinal tract. New gene transfer approaches based either on blocking pro-inflammatory cytokines or overexpression of anti-inflammatory cytokines, particularly interleukin-10, showed promising results in animal models of IBD. Future studies analyzing the effects of cytokine-targeted gene therapy in patients are eagerly awaited.
Curr Opin Mol Ther 2003 Oct
PMID:Inflammatory bowel disorders: gene therapy solutions. 1460 18

Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.
Hum Mol Genet 2004 Jan 01
PMID:Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. 1461 70

Secretory antibodies protect mucosal surfaces from ingested, inhaled and sexually transmitted pathogens. The polymeric immunoglobulin receptor (pIgR) transports antibodies across mucosal epithelia into external secretions. We and others have identified a region of the human polymeric immunoglobulin receptor gene (locus PIGR) that is sufficient for basal transcriptional activity. An E-Box motif, which binds transcription factors of the basic helix-loop-helix/leucine zipper (bHLH/zip) family, was identified as a major regulatory element in the PIGR gene promoter. Transient transfection of PIGR promoter reporter plasmids in intestinal epithelial cell (IEC) lines suggested that the transcription factors upstream stimulatory factor (USF) and c-Myc may exert opposing effects on PIGR promoter activity. Mutations within and flanking the E-Box that favored USF binding enhanced promoter activity, while mutations that favored c-Myc binding reduced promoter activity. Ectopic expression of USF1 or USF2 enhanced PIGR promoter activity, while exogenous c-Myc did not. Electrophoretic mobility shift assays (EMSA) demonstrated that USF1 and USF2 bound to the E-Box motif as homo- and heterodimers. Chromatin immunoprecipitation (ChIP) demonstrated that USF proteins bind the PIGR promoter in vivo, which is enriched in acetylated histones. E-Box motifs are commonly observed in promoters of genes that are highly expressed in the human colon. Genes that are down-regulated in colorectal cancer, including PIGR, frequently have non-canonical E-Boxes, while genes that are up-regulated in colorectal cancer generally have canonical E-Boxes. The results of our experiments may shed light on the mechanisms of dysregulated expression of pIgR in inflammatory bowel disease and colorectal cancer, diseases associated with aberrant expression of c-Myc.
Mol Immunol 2004 Jan
PMID:Upstream stimulatory factor but not c-Myc enhances transcription of the human polymeric immunoglobulin receptor gene. 1464 95

Epimorphin is a membrane-associated protein that has been postulated to regulate epithelial morphogenesis in several tissues. However, epimorphin expression in the human intestine has not been fully investigated. In this study, we investigated epimorphin expression in the inflamed mucosa of inflammatory bowel disease (IBD). Tissue samples were obtained surgically from patients with active ulcerative colitis (UC) (n=5) and active Crohn's disease (CD) (n=5). Epimorphin and alpha-smooth muscle actin (SMA) were stained immunohistochemically. Epimorphin expression in human intestinal subepithelial myofibroblasts (SEMFs) was analyzed by Western and Northern blotting. In the normal colon, epimorphin expression was detected partly in the alpha-SMA-positive cells under the epithelial cells. Epimorphin was also expressed in alpha-SMA-positive cells in the capillary wall. In the inflamed mucosa of UC and CD patients, epimorphin expression was not altered. In isolated human SEMFs, epimorphin was detected as a single band of molecular weight 34-kDa under reducing and non-reducing conditions. In intestinal SEMFs, epimorphin mRNA expression was not affected by inflammatory cytokines and growth factors. Epimorphin was constitutively expressed in the normal colonic mucosa, and this was not altered in the inflamed mucosa of IBD patients. The localization of epimorphin may indicate a potential role in maintaining normal tissue structure in normal and IBD mucosa.
Int J Mol Med 2004 Jan
PMID:Epimorphin expression in human colonic myofibroblasts. 1465 71

Lymphatic vessels in the colon are normally distributed beneath the muscularis mucosae with rare branches reaching through the muscularis mucosae to the most basal aspect of the colonic crypts. In chronic inflammatory bowel disease demonstrating acute inflammation and architectural disarray, lymph vessel proliferation is seen within the lamina propria and within the submucosa. We analyzed the number and distribution of lymphatic vessels within the lamina propria and submucosa in chronic active and treated ulcerative colitis with restoration of architecture by immunostaining with D2-40, a specific monoclonal antibody against lymphatic vessels. We found significantly increased numbers of lymph vessels in chronic active ulcerative colitis both within the lamina propria and the submucosa as compared to normal mucosa. Numbers of lymph vessels in lamina propria were highest in severe chronic active ulcerative colitis and less in moderate and minimal residual disease with minimal architectural disarray (p<0.05). Lymph vessels in the submucosa were increased significantly above normal values in both severe, moderate and minimal residual disease. We conclude that lymph vessel distribution in chronic active ulcerative colitis extends into the lamina propria. With restoration of architectural morphology, the integrity of the lamina propria in regards to the distribution of lymph vessels is restored.
Int J Mol Med 2004 Feb
PMID:Proliferation of D2-40-expressing intestinal lymphatic vessels in the lamina propria in inflammatory bowel disease. 1471 25

Strong epidemiological evidence for a genetic contribution to pathogenesis in inflammatory bowel disease (IBD) has stimulated efforts to identify susceptibility genes for both of its major clinical forms, Crohn's disease and ulcerative colitis. Genome scans for linkage have indicated multiple regions of interest, but replication of these has been limited. The detection of linkage on chromosome 16 (IBD1) led to the unequivocal identification of the NOD2 gene (now called CARD15) as a susceptibility gene for Crohn's disease. This seminal discovery has provided proof of principle for positional cloning and candidate gene approaches to identify IBD genes. It has also led to useful strategic insights in complex disease genetics, and generated new directions in the investigation of the molecular pathways to pathogenesis. Linkage and association studies have also provided strong support for IBD susceptibility genes on chromosomes 5q31, 6p21 and 19p, while loci of interest at 3p, 3q and 14q require further follow-up. Although important obstacles to further progress will need to be overcome, the successes of the past 2 years suggest that a detailed description of the genetic basis of inflammatory bowel disease is a realistic goal.
Hum Mol Genet 2004 Apr 01
PMID:Genetics of inflammatory bowel disease: progress and prospects. 1476 25

Crohn's disease and ulcerative colitis (the inflammatory bowel diseases) have a strong genetic component. Although over 20 putative susceptibility loci have been identified by individual genome scans, the majority of these loci have not been replicated. Many individual studies are at the lower limit of acceptable power for complex disease linkage analysis. Genome scan meta-analysis (GSMA), by use of sample sizes an order of magnitude greater than individual linkage studies, has increased power to detect novel loci, may confirm or refute regions detected in smaller individual studies, and enables regions to be prioritized for further gene identification efforts. Genome scan data (markers, significance scores) were obtained from 10 separate studies and meta-analysis was performed using the GSMA method. These studies comprised 1952 inflammatory bowel disease, 1068 Crohn's disease and 457 ulcerative colitis affected relative pairs. Study results were divided into 34 cM chromosomal bins, ranked, weighted by study size, summed across studies and bin-by-bin significance obtained by simulation. A region on chromosome 6p (containing the HLA) met genome wide significance for inflammatory bowel disease. Loci meeting suggestive significance for inflammatory bowel disease were 2q, 3q, 5q, 7q and 16 (NOD2/CARD15 region); Crohn's disease, 2q, 3q, 6p, 16 (NOD2/CARD15 region), 17q, 19p; and ulcerative colitis, 2q. Clustering of adjacent bins was observed for chromosomes 6p, 16, 19p. The meta-analysis has identified novel loci and prioritized genomic regions for further gene identification studies.
Hum Mol Genet 2004 Apr 01
PMID:Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. 1497 56


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>