Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0010346 (Crohn's disease)
 21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate the biological dysregulation underlying two forms of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD), we examined global gene expression profiles of inflamed colonic tissue using DNA microarrays. Our results identified several genes with altered expression not previously linked to IBD. In addition to the expected upregulation of various cytokine and chemokine genes, novel immune function-related genes such as IGHG3, IGLL2 and CD74, inflammation-related lipocalins HNL and NGAL, and proliferation-related GRO genes were over-expressed in UC. Certain cancer-related genes such as DD96, DRAL and MXI1 were differentially expressed only in UC. Other genes over-expressed in both UC and CD included the REG gene family and the calcium-binding S100 protein genes S100A9 and S100P. The natural antimicrobial defensin DEFA5 and DEFA6 genes were particularly over-expressed in CD. Overall, significant differences in the expression profiles of 170 genes identified UC and CD as distinct molecular entities. The genomic map locations of the dysregulated genes may identify novel candidates for UC and CD genetic susceptibility.
 ...
PMID:Ulcerative colitis and Crohn's disease: distinctive gene expression profiles and novel susceptibility candidate genes. 1118 68

Human alpha-defensins contribute to local intestinal host defense as part of innate immunity and may be of major relevance in microbial infection and chronic inflammatory bowel disease. The objective was to investigate human defensin 5 and 6 (HD-5, HD-6) mRNA expression by RT-PCR from colonic biopsies and peptide expression by immunohistochemistry from colonic resections under basal and inflammatory conditions. Both alpha-defensins were induced by proinflammatory cytokines in cell culture. HD-5 mRNA expression was enhanced in both idiopathic and nonidiopathic inflammatory states of the large bowel [32% of control vs 73% of unspecific colitis, 69% of Crohn's disease (CD) and 73% of ulcerative colitis (UC)], whereas HD-6 was specifically related to CD and UC (14% in controls vs 20% in unspecific coltis, 49% in CD and 42% in UC). Immunohistochemistry confirmed the presence of HD-5 in colonic epithelium. Antimicrobial peptides in the colon may be of importance in maintaining the mucosal barrier and controlling microbial invasion in inflammatory bowel diseases.
 ...
PMID:Innate immunity and colonic inflammation: enhanced expression of epithelial alpha-defensins. 1206 12

The impact of chronic inflammation on the expression of human alpha-defensins 5 and 6 (HD-5, HD-6), beta-defensins 1 and 2 (hBD-1, hBD-2) and lysozyme in epithelial cells of small and large intestine was investigated. Intestinal specimens from 16 patients with ulcerative colitis (UC), 14 patients with Crohn's disease (CD) and 40 controls with no history of inflammatory bowel disease were studied. mRNA expression levels of the five defence molecules were determined in freshly isolated epithelial cells by real-time quantitative RT-PCR. Specific copy standards were used allowing comparison between the expression levels of the different defensins. HD-5 and lysozyme protein expression was also studied by immunohistochemistry. Colonic epithelial cells from patients with UC displayed a significant increase of hBD-2, HD-5, HD-6 and lysozyme mRNA as compared to epithelial cells in controls. Lysozyme mRNA was expressed at very high average copy numbers followed by HD-5, HD-6, hBD-1 and hBD-2 mRNA. HD-5 and lysozyme protein was demonstrated in metaplastic Paneth-like cells in UC colon. There was no correlation between hBD-2 mRNA levels and HD-5 or HD-6 mRNA levels in colon epithelial cells of UC patients. Colonic epithelial cells of Crohn's colitis patients showed increased mRNA levels of HD-5 and lysozyme mRNA whereas ileal epithelial cells of Crohn's patients with ileo-caecal inflammation did not. Chronic inflammation in colon results in induction of hBD-2 and alpha-defensins and increased lysozyme expression. hBD-1 expression levels in colon remain unchanged in colitis. The high antimicrobial activity of epithelial cells in chronic colitis may be a consequence of changes in the epithelial lining, permitting adherence of both pathogenic bacteria and commensals directly to the epithelial cell surface.
 ...
PMID:Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis. 1251 91

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.
 ...
PMID:Alpha-defensins in the gastrointestinal tract. 1456 93

Defensins are endogenous antimicrobial peptides with a broad activity spectrum. Even at micromolar concentrations gramnegative and grampositive bacteria, but also mycobacteria, as well as fungi (candida), viruses (herpes) and protozoa (giardia lamblia) are destroyed. As part of the innate immune system defensins are expressed by the intestinal epithelium and contribute to the maintenance of the mucosal barrier. This barrier appears to be defective in inflammatory bowel diseases since on one hand, the immune response is directed against the "normal" luminal bacterial flora and on the other hand, mucosal adherent and invasive bacteria have been observed in these diseases. A defective defensin expression may well explain these phenomena. Indeed, Crohn's disease of the terminal ileum, especially if associated with a NOD2 mutation, is characterised by a diminished alpha-defensin (human defensin 5 and 6) expression, and in inflamed Crohn's colitis, in contrast to ulcerative colitis, the beta-defensin (human beta-defensins 2 and 3) response is reduced. Through a deficient chemical mucosal barrier this defect could lead to increased bacterial invasion into the intestinal mucosa and might well explain an adequate inflammatory response. Although the final proof that this deficient defensin response leads to a reduced antibacterial activity of the intestinal mucosa is still lacking, the most plausible concept of pathogenesis of Crohn's disease is a defensin deficiency syndrome.
 ...
PMID:[The role of defensins in the pathogenesis of chronic-inflammatory bowel disease]. 1509 25

alpha-Defensin is an antimicrobial peptide which plays an important role in innate immunity. Human defensin (HD)-5 is stored in the Paneth cells of the small intestine as a pro-form and is cleaved by trypsin, which is co-secreted from the Paneth cell granules. The mature HD-5 is protected from further digestion by the proteolysis enzyme. We generated both recombinant HD-5 and proHD-5, and the reduced form of each peptide in order to determine their physiological roles of the disulfide bonds. The reduced proHD-5 attenuated the bactericidal activity and the stability against the trypsin digestion. Human defensin was protected from the enzymatic degradation by disulfide bridges. We further purified the HD-5 with a disulfide variation in the small intestine of Crohn's disease patients. The HD-5 was sensitive to the trypsin treatment. These observations evidently predict that a defensin deficiency may be caused by a disulfide disorder in the disease.
 ...
PMID:Denatured human alpha-defensin attenuates the bactericidal activity and the stability against enzymatic digestion. 1748 39

Ileal Crohn's disease (CD), a chronic mucosal inflammation, is characterized by two pertinent features: a specific decrease of Paneth cell-produced antimicrobial alpha-defensins and the presence of mucosal-adherent bacteria. A mutation in NOD2, the muramyl dipeptide recognition receptor, is found in some patients, which leads to an even more pronounced alpha-defensin decrease. However, the underlying mechanism remains unclear for the majority of patients. In this study, we report a reduced expression in ileal CD of the Wnt-signaling pathway transcription factor Tcf-4, a known regulator of Paneth cell differentiation and alpha-defensin expression. Within specimens, the levels of Tcf-4 mRNA showed a high degree of correlation with both HD5 and HD6 mRNA. The levels of Tcf-4 mRNA were decreased in patients with ileal disease irrespective of degree of inflammation, but were not decreased in colonic CD or ulcerative colitis. As a functional indicator of Tcf-4 protein, quantitative binding analysis with nuclear extracts from small intestine biopsies to a Tcf-4 high-affinity binding site in the HD-5 and HD-6 promoters showed significantly reduced activity in ileal CD. Furthermore, a causal link was shown in a murine Tcf-4 knockout model, where the comparably reduced expression of Tcf-4 in heterozygous (+/-) mice was sufficient to cause a significant decrease of both Paneth cell alpha-defensin levels and bacterial killing activity. Finally, the association between Paneth cell alpha-defensins and Tcf-4 was found to be independent of the NOD2 genotype. This new link established between a human inflammatory bowel disease and the Wnt pathway/Tcf-4 provides a novel mechanism for pathogenesis in patients with ileal CD.
 ...
PMID:The Paneth cell alpha-defensin deficiency of ileal Crohn's disease is linked to Wnt/Tcf-4. 1770 25

To determine the genetic program mediating and maintaining the change from susceptibility to Crohn's disease (CD) to ongoing tissue destruction and loss of function, we utilized Affymetrix HG U95 AV2 Gene Chips and analyzed unpooled surgical CD colon specimens from adult patients. Using the patient as his own genetic filter we examined involved versus uninvolved adjacent areas, comparing results within one individual and then performing analysis comparing results between four individuals. Our results interrogated twice as many genes than the previous studies that used pooled unmatched specimens. We identified a limited set of nine genes upregulated in all four patients, and one gene (PTN) as downregulated. Several of the genes, including DEFA6, PAP, REG1A, REG1B, and phospholipase A2 had been implicated in previous studies, supporting their key role in CD. In 3 of 4 patients, 24 genes were upregulated in diseased areas, including DEFA5, IL-8, MMP-1, S100 calcium binding protein, and MGSA. Additional new candidate genes were identified, including DMT1, SERPINA1, GW112, and iNOS. The use of the unpooled samples allowed the detection of significant interindividual differences in expression of many other genes, supporting disease heterogeneity in CD. Results with select genes were confirmed with RT-PCR studies, as well as on biopsy samples from pediatric patients. We have determined a common profile of "late" CD, and also demonstrated the potential variability, suggesting possible differences in etiology, triggers, and the need for more individualized management. Additional studies to investigate protein expression of these candidate genes should be undertaken.
 ...
PMID:Gene expression profiles of late colonic Crohn's disease. 1808 81

Human defensin (HD)-5 is an antimicrobial peptide expressed in small intestinal Paneth cells, and alterations in HD-5 expression may be important in Crohn's disease (CD) pathogenesis. Levels of HD-5 in Paneth cells and ileostomy fluid from control and CD patients were studied by quantitative immunodot analysis, immunohistochemistry, acid urea-polyacrylamide gel electrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis Western blotting, reverse phase-high performance liquid chromatography, N-terminal amino acid sequencing, and ES-QToF mass spectrometry. In both control and CD patients, HD-5 in Paneth cell extracts was present almost exclusively in the precursor form. HD-5 levels in ileostomy fluid were lower in CD patients (n = 51) than in controls (n = 20): median (range), 7.9 (5.5 to 35.0) microg/ml versus 10.5 (6.0 to 30.4) microg/ml; P = 0.05; this difference was most marked in CD patients with homozygous/compound heterozygous mutations in NOD2 (P = 0.03). In control ileostomy fluid, HD-5 was present in the mature form only. In contrast, CD patient ileostomy fluid contained both precursor and mature forms of HD-5, with the majority present in a complex with trypsin, chymotrypsinogen/chymotrypsin, and alpha1-anti-trypsin. Pro-HD-5 was not associated with trypsin or chymotrypsinogen in Paneth cell extracts. In conclusion, pro-HD-5 in the intestinal lumen is processed by trypsin in a complex in which chymotrypsinogen is also cleaved for activation. The persistence of this complex in CD may be attributable to increased luminal levels of proteinase inhibitors such as alpha1-anti-trypsin.
 ...
PMID:Impaired luminal processing of human defensin-5 in Crohn's disease: persistence in a complex with chymotrypsinogen and trypsin. 1825 45

Reduced expression of Paneth cell antimicrobial alpha-defensins, human defensin (HD)-5 and -6, characterizes Crohn's disease (CD) of the ileum. TCF-4 (also named TCF7L2), a Wnt signalling pathway transcription factor, orchestrates Paneth cell differentiation, directly regulates the expression of HD-5 and -6, and was previously associated with the decrease of these antimicrobial peptides in a subset of ileal CD. To investigate a potential genetic association of TCF-4 with ileal CD, we sequenced 2.1 kb of the 5' flanking region of TCF-4 in a small group of ileal CD patients and controls (n = 10 each). We identified eight single nucleotide polymorphisms (SNPs), of which three (rs3814570, rs10885394, rs10885395) were in linkage disequilibrium and found more frequently in patients; one (rs3814570) was thereby located in a predicted regulatory region. We carried out high-throughput analysis of this SNP in three cohorts of inflammatory bowel disease (IBD) patients and controls. Overall 1399 healthy individuals, 785 ulcerative colitis (UC) patients, 225 CD patients with colonic disease only and 784 CD patients with ileal involvement were used to determine frequency distributions. We found an association of rs3814570 with ileal CD but neither with colonic CD or UC, in a combined analysis (allele positivity: OR 1.27, 95% CI 1.07 to 1.52, p = 0.00737), which was the strongest in ileal CD patients with stricturing behaviour (allele frequency: OR 1.32, 95% CI 1.08 to1.62, p = 0.00686) or an additional involvement of the upper GIT (allele frequency: OR 1.38, 95% CI 1.03 to1.84, p = 0.02882). The newly identified genetic association of TCF-4 with ileal CD provides evidence that the decrease in Paneth cell alpha-defensins is a primary factor in disease pathogenesis.
 ...
PMID:Genetic variants of Wnt transcription factor TCF-4 (TCF7L2) putative promoter region are associated with small intestinal Crohn's disease. 1922


1 2 3 Next >>