Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009324 (ulcerative colitis)
 17,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Initiation and perpetuation of the inflammatory intestinal responses in inflammatory bowel disease (IBD) may result from an exaggerated host defense reaction of the intestinal epithelium to endogenous lumenal bacterial flora. Intestinal epithelial cell lines constitutively express several functional Toll-like receptors (TLRs) which appear to be key regulators of the innate response system. The aim of this study was to characterize the expression pattern of TLR2, TLR3, TLR4, and TLR5 in primary intestinal epithelial cells from patients with IBD. Small intestinal and colonic biopsy specimens were collected from patients with IBD (Crohn's disease [CD], ulcerative colitis [UC]) and controls. Non-IBD specimens were assessed by immunofluorescence histochemistry using polyclonal antibodies specific for TLR2, TLR3, TLR4, and TLR5. Primary intestinal epithelial cells (IEC) of normal mucosa constitutively expressed TLR3 and TLR5, while TLR2 and TLR4 were only barely detectable. In active IBD, the expression of TLR3 and TLR4 was differentially modulated in the intestinal epithelium. TLR3 was significantly downregulated in IEC in active CD but not in UC. In contrast, TLR4 was strongly upregulated in both UC and CD. TLR2 and TLR5 expression remained unchanged in IBD. These data suggest that IBD may be associated with distinctive changes in selective TLR expression in the intestinal epithelium, implying that alterations in the innate response system may contribute to the pathogenesis of these disorders.
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PMID:Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. 1108 26

Genes encoding for receptors of the innate immune system are potential candidates for susceptibility to inflammatory bowel disease, e.g., mutations in the cytosolic receptor NOD2/CARD15 were associated with Crohn's disease. Herein, two mutations of the Toll-like receptor (TLR)-4 gene (Asp299Gly and Thr399Ile) resulting in impaired lipopolysaccharide signaling, the -159C/T promotor polymorphism of the CD14 gene, polymorphisms of the lipopolysaccharide binding protein gene and the bactericidal permeability increasing protein gene were evaluated in 102 patients with Crohn's disease, 98 patients with ulcerative colitis and 145 healthy controls. The allele and carrier frequencies for the Thr399Ile mutation in TLR4 gene were significantly increased in ulcerative colitis when compared to the controls (P = 0.014 and P = 0.018, respectively). None of the other five polymorphisms was associated with inflammatory bowel disease. In conclusion, a novel association between a functional polymorphism in TLR4 and ulcerative colitis is reported. This observation underscores the importance of impaired innate immunity in inflammatory bowel disease.
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PMID:Polymorphisms of the lipopolysaccharide-signaling complex in inflammatory bowel disease: association of a mutation in the Toll-like receptor 4 gene with ulcerative colitis. 1520 85

The interleukin-2-deficient (IL-2(-/-)) mouse model of ulcerative colitis was used to test the hypothesis that colonic epithelial cells (CEC) directly respond to bacterial antigens and that alterations in Toll-like receptor (TLR)-mediated signaling may occur during the development of colitis. TLR expression and activation of TLR-mediated signaling pathways in primary CEC of healthy animals was compared with CEC in IL-2(-/-) mice during the development of colitis. In healthy animals, CEC expressed functional TLR, and in response to the TLR4 ligand LPS, proliferated and secreted the cytokines IL-6 and monocyte chemoattractant protein-1 (MCP-1). However, the TLR-responsiveness of CEC in IL-2(-/-) mice was different with decreased TLR4 responsiveness and augmented TLR2 responses that result in IL-6 and MCP-1 secretion. TLR signaling in CEC did not involve NF-kappaB (p65) activation with the inhibitory p50 form of NF-kappaB predominating in CEC in both the healthy and inflamed colon. Development of colitis was, however, associated with the activation of MAPK family members and upregulation of MyD88-independent signaling pathways characterized by increased caspase-1 activity and IL-18 production. These findings identify changes in TLR expression and signaling during the development of colitis that may contribute to changes in the host response to bacterial antigens seen in colitis.
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PMID:Toll-like receptor-mediated responses of primary intestinal epithelial cells during the development of colitis. 1549 80

Research efforts in the inflammatory bowel diseases have been uniquely successful in identifying genetic linkage regions likely containing susceptibility genes for Crohn's disease and ulcerative colitis. In two of these regions, definitive gene associations have been established, namely for the NOD2/CARD15 gene on chromosome 16 (IBD1) and the OCTN1/SLC22A4-OCT/SLC22A5 genes on chromosome 5q (IBD5), both conferring increased risk for developing Crohn's disease. Recently, significant gene associations have been reported for additional genes, including DLG5, MDR1, and TLR4 as well. The NOD2/CARD15 gene mutations are associated with ileal disease location and a modestly earlier age of onset compared with NOD2/CARD15 wild-type Crohn's disease patients. Future progress in the genetics of inflammatory bowel disease will likely involve systematic phenotyping, including the incorporation of clinical subtypes and novel biomarkers. The ultimate goal of genetic research in inflammatory bowel disease is to identify the earliest biologic pathways that are altered, resulting in disease pathogenesis. Identification of these key pathways will potentially highlight novel therapeutic targets.
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PMID:Advances in the genetics of inflammatory bowel disease. 1552 76

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn's disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.
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PMID:Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn's disease patients. 1601 May 82

The aim of this study was to evaluate the expression pattern of Toll-like receptors (TLRs) in the pouch mucosa of ulcerative colitis patients in comparison with that in the ileum mucosa of noninflammatory bowel disease patients. Pouch mucosal biopsy specimens were collected from postoperative patients who had undergone surgery for ulcerative colitis. Normal ileum specimens were collected from colon cancer patients. The specimens were assessed by immunofluorescence histochemistry using TLR2, TLR3, TLR4, and TLR5 polyclonal antibodies. The normal ileal mucosa constitutively expressed TLR3 and TLR5, whereas TLR2 and TLR4 were barely detectable. In the mucosa of active pouchitis, TLR2 and TLR4 was strongly upregulated, and TLR4 was upregulated even in a noninflamed pouch. No TLR3 or TLR5 expression was detectable. These data suggest that pouchitis may be associated with distinctive changes in selective TLR expression in the pouch mucosa, and that TLR4 alterations in the innate response system may contribute to the pathogenesis of these disorders in particular.
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PMID:The expression patterns of Toll-like receptors in the ileal pouch mucosa of postoperative ulcerative colitis patients. 1649 44

Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with a genetic background. Genes related to the innate immune response have been observed to be involved. Polymorphisms of Toll-like receptor 4 (TLR4) and CARD15/NOD2 are thought to be involved in the pathogenesis of inflammatory bowel disease (IBD). There is no information about the frequency of these polymorphisms in South American and Chilean populations. Aim. To investigate the distribution of CARD15/NOD2 (Arg702Trp, Gly908Arg and Leu1007fsinsC) and TLR4 (Asp299Gly) polymorphisms in Chilean patients with IBD. Methods. DNA was obtained from 22 CD, 22 UC patients and 20 healthy individuals. Genotyping was performed by allele-specific PCR and by PCR-RFLP analysis. Clinical and demographic features were characterized. Results. Among the CD patients, the clinical pattern was deemed inflammatory in 14, while five had penetrating and five stricturing, variants. One patient had esophageal involvement, five perianal, seven ileal and in 16 the colon was involved. Among the UC patients, two had proctitis, two proctosigmoiditis, four left-sided colitis and 14 pancolitis. NOD2/CARD15 analysis revealed the presence of the 702Trp allele in two CD patients (both heterozygotes), 1007fsinsC in one CD patient (heterozygote) while 908Arg was found in one UC patient. The 299Gly TLR4 allele was identified in one UC and one CD patient. Conclusion. This genetic study shows that the alleles frequently associated with IBD (1007fsinsC, 908Arg and 702Trp in NOD2/CARD15 and 299Gly TLR4) have a low incidence in Chilean, IBD patients, which is similar to European populations. It is possible that, in addition to environmental factors, other genetic polymorphisms may be involved in the pathogenesis of the disease in Chilean, IBD patients.
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PMID:NOD2/CARD15 and Toll-like 4 receptor gene polymorphism in Chilean patients with inflammatory bowel disease. 1684 31

Factors underlying genetic predisposition for development of sporadic colorectal cancer are largely unknown. The fact that this cancer is more common in patients suffering from inflammatory bowel disease raises the question of the relationship between chronic inflammation and cancer. Toll-like receptors 2 (TLR2) and 4 (TLR4) are critical in initiating innate immune response and inflammation toward various bacteria commonly found in the intestine. Recent evidence about the association of polymorphisms in these genes with ulcerative colitis and Crohn's disease, as well as other inflammatory conditions, was the basis for our investigation of their role in sporadic colorectal cancer. We assessed genotype and allele frequencies of TLR2 GT microsatelite polymorphism, TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms in 89 colorectal cancer patients and 88 age- and sex-matched controls. The frequency of TLR2 GT microsatelite alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p = 0.001, respectively), while the frequency of the allele with 31 GT repeats was increased (p = 0.0147) in patients. The mutant allele Asp299Gly of TLR4 gene was slightly more frequent in colorectal cancer patients (p = 0.0269). In conclusion, we report an association of microsatelite GT polymorphisms of TLR2 gene and Asp299Gly polymorphism of the TLR4 gene with sporadic colorectal cancer among Croatians.
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PMID:Microsatelite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer. 1687 99

Geographic and ethnic variations in ulcerative colitis and Crohn's disease frequency suggest that environmental factors affect disease risk. Prevention of parasitic worms (helminths) through improved hygiene may be one factor leading to the increased disease prevalence. Helminths alter host mucosal and systemic immunity. Animals exposed to helminths are protected from experimental colitis and other immunological diseases, and helminthic colonization can be used to treat ongoing murine and human disease. Helminths induce mucosal T cells to make Th2 and regulatory cytokines. Helminth-induced mucosal IL4, TGFbeta, and IL10 likely are part of the protective process. Helminths affect pathways of innate immunity like TLR4 expression and function. Worms also induce various regulatory-type T-cell subsets in the gut that limit effector T-cell growth and function. These effects of once ever-present helminths may have protected people from immune-mediated illnesses like inflammatory bowel disease.
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PMID:Helminths and mucosal immune modulation. 1705 16

The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.
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PMID:The role of the Toll receptor pathway in susceptibility to inflammatory bowel diseases. 1753 33


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