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)

Mutations in apc which lead to activation of the Wnt signaling pathway are a hallmark of sporadic colon cancers but occur infrequently in colon cancers arising in patients with inflammatory bowel disease (IBD). There is evidence, however, that other components of the Wnt pathway may be altered in IBD-related colon cancer. In this study, we examined the expression the Wnt pathway components frizzled (Fz), the cell surface receptor, and disheveled (DVL), a family of cytoplasmic signal transduction molecules, in IBD and IBD-related colon cancer. Paraffin sections of normal and malignant colon tissues were obtained from patients with a history of ulcerative colitis and from controls with sporadic colon cancer. Tissue sections were stained with antibodies directed against Fz1/2 receptors and DVL1, DVL2 and DVL3 and antigen expression visualized by immunohistochemistry. Fz1/2 receptors were minimally expressed in normal IBD mucosa, were not expressed in IBD colon cancer, but exhibited strong expression in dysplastic tissues adjacent to the cancers. DVL1 was not expressed in IBD normal mucosa or normal mucosa from non-IBD patients, but was expressed in all cancers. DVL2 and DVL3 were expressed in all normal mucosa samples tested, and in sporadic colon cancer, but were not expressed in colon cancers arising in IBD patients. The characteristics of Fz and DVL expression in IBD tissues reported herein provides evidence of the importance of Wnt signaling in IBD and IBD-related colon cancer and, specifically, the significance of non-APC components of this pathway. Fz may serve as a marker for dyspasia in IBD patients and DVL1 is a potential therapeutic target for IBD-related colon cancer.
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PMID:Expression of Wnt pathway components frizzled and disheveled in colon cancer arising in patients with inflammatory bowel disease. 1767 21

We investigated the expression of the neurotensin high-affinity receptor 1 (NTS1) during inflammatory bowel disease (IBD)-related colorectal oncogenesis, in colonic samples from 30 patients with IBD-related adenocarcinomas, dysplasias, and inflammatory mucosa (IM). The percentage of NTS1-positive epithelial cells progressively increased from the inflammatory condition to adenocarcinoma and was significantly higher in adenocarcinomas than in IM (p=0.0169). In parallel, the percentage of neurotensin (NT)-positive epithelial cells increased during the IBD-related oncogenesis. Finally, as NTS1 is a ss-catenin inducible gene, we found that a number of preneoplastic lesions and adenocarcinomas co-expressed NTS1 and beta-catenin without NT expression. Therefore, this study suggests two pathways of NTS1 overexpression during IBD-related oncogenesis: one triggered by NT overexpression, and a second associated with an activation of the APC/beta-catenin pathway, these two pathways being not mutually exclusive.
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PMID:Over-expression of neurotensin high-affinity receptor 1 (NTS1) in relation with its ligand neurotensin (NT) and nuclear beta-catenin in inflammatory bowel disease-related oncogenesis. 1787 Feb 7

Here, we report on a patient with squamous cell carcinoma (SCC) arising from recurrent anal fistula. The patient was a 57-year-old woman who had 32-year history of having a recurrent perianal abscesses that ruptured spontaneously. Six months before her admission to our hospital, anal pain developed. She had no history of inflammatory bowel disease. Physical examination revealed three external fistulous openings at the two o'clock position, 2 cm from the anal verge. One internal opening in the lower rectum was found with proctoscopy. The patient underwent fistulectomy. Microscopic examination showed SCC arising from the anal fistula, which was accompanied by vessel invasion. The tumor was observed to be continuous from the external opening but was not exposed to the internal opening of the rectal mucosa. Because human papillomavirus (HPV) infection was suspected, immunohistochemical analysis was performed, but showed no HPV infection. Two weeks after fistulectomy, abdominoperineal resection with lymph node dissection was performed. Histopathological examination revealed no remnant cancer tissue or lymph node metastasis. She was discharged after surgery without complications. Eight years after the operation, she complained of constant pain during micturition. Urological examination revealed urinary bladder cancer, and transurethral resection of the bladder tumor was performed. Histopathological examination revealed transitional cell carcinoma of the urinary bladder. Two years later, the patient died of metastatic urinary bladder cancer, without recurrence of the fistula cancer. Because the patients mother had died of urinary bladder cancer and she herself had metachronous urinary bladder cancer in addition to fistula cancer, we investigated whether microsatellite instability (MSI) and chromosomal instability correlated with fistula cancer development. Immunohistochemical analysis of formalin-fixed, paraffin-embedded surgical tumor specimens for p53, MLH1, and MSH2 was performed. The tumor specimens showed no MLH1 expression but did show normal MSH2 expression. p53 was not expressed. Five microsatellite loci were examined using the tumor specimens to detect MSI, namely two loci with mononucleotide runs (i.e., BAT25 and BAT26) and three loci with dinucleotide repeats (i.e., APC, Mfd15, and D2S123). The tumor specimens showed alternations in the repeated sequences of two loci (i.e., BAT26 and D2S123). As a result, the tumor was classified as MSI-H (high) according to the Bethesda criteria. Our patient had MSI and one of the smallest reported SCCs arising from recurrent anal fistulae.
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PMID:Squamous cell carcinoma arising from recurrent anal fistula. 1787 4

Traditionally described as a major anti-coagulant system, the protein C (PC) pathway, consisting of thrombomodulin, the endothelial cell protein C receptor and activated PC (APC), is gaining increasing attention as an important regulator of microvascular inflammation. Although they possess several anti-inflammatory and cytoprotective functions, the expression and function of the components of the PC pathway is downregulated during inflammation. Recent evidence suggests that the PC pathway is defective in patients with inflammatory bowel disease (IBD) and that restoring its function has anti-inflammatory effects on cultured intestinal microvascular endothelial cells and in animal models of colitis. Here, we propose that the PC pathway has an important role in governing intestinal microvascular inflammation and might provide a novel therapeutic target in the management of IBD.
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PMID:The protein C pathway in inflammatory bowel disease: the missing link between inflammation and coagulation. 1845 95

Recent evidence implicating tissue factor and the protein C pathway in the hypercoagulable state associated with intestinal inflammation suggests that thrombin is likely to contribute to this response. The objective of this study was to assess the role of thrombin in the extraintestinal thrombosis associated with experimental colitis. Thrombus formation was quantified in microvessels of the cremaster muscle in mice with dextran sodium sulfate (DSS)-induced colonic inflammation. The light/dye endothelial injury model was used to elicit thrombus formation in DSS colitic mice treated with either hirudin, heparin, or antithrombin III. The initiation and propagation/stabilization phases of thrombus formation were quantified using the time of onset of the thrombus and time to blood flow cessation, respectively. Thrombus formation was accelerated in arterioles of DSS colitic mice, as exhibited by significant reductions in the time of thrombus initiation and propagation/stabilization. Colitic mice treated with hirudin, heparin, or antithrombin III did not exhibit a significant change in the time of onset of the thrombus compared with untreated colitic mice. However, all three antithrombin agents largely prevented the DSS-induced reduction in the time to flow cessation following light/dye injury, with hirudin offering complete protection. These findings indicate that thrombin plays a major role in the extraintestinal thrombus formation associated with experimental colitis. Thrombin appears to contribute to the propagation/stabilization, rather than initiation, phase of the colitis-associated thrombogenesis at the distant vascular site. The results support the therapeutic use of antithrombin agents for reducing the risk of thromboembolism in patients with inflammatory bowel disease.
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PMID:Thrombin mediates the extraintestinal thrombosis associated with experimental colitis. 1877 59

The pathogenesis of human inflammatory bowel disease (IBD) and most experimental models of IBD is dependent on the activation and expansion of CD4(+) T cells via interaction with mucosal APCs. The costimulatory receptor CD70 is transiently expressed on the surface of conventional dendritic cells, but is constitutively expressed by a unique APC population in the intestinal lamina propria. We used two experimental IBD models to evaluate whether interfering the interaction between CD70 and its T cell ligand CD27 would affect the development of colitis. Adoptive transfer of naive CD27-deficient CD45RB(high) CD4(+) T cells into Rag-1(-/-) mice resulted in significantly less disease than when wild-type CD45RB(high)CD4(+) T cells were used. Moreover, a monoclonal anti-CD70 Ab prevented the disease caused by the transfer of wild-type CD45RB(high) CD4(+) T cells into Rag-1(-/-) mice and the same Ab also ameliorated an established disease. The colitis associated proinflammatory cytokines IL-6, TNF-alpha and IFN-gamma were significantly reduced after anti-CD70 Ab treatment, suggesting an overall reduction in inflammation due to blockade of pathogenic T cell expansion. Anti-CD70 Ab treatment also suppressed trinitrobenzene sulfonic acid-induced colitis in SJL/J mice. Because anti-CD70 Ab treatment suppressed multiple proinflammatory cytokines, this may be a more potent therapeutic approach for IBD than blockade of individual cytokines.
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PMID:Blocking CD27-CD70 costimulatory pathway suppresses experimental colitis. 1952 96

Alterations in expression of protein C (PC) pathway components have been identified in patients with active inflammatory disease states. While the PC pathway plays a pivotal role in regulating coagulation and fibrinolysis, activated PC (aPC) also exhibits cytoprotective properties. For example, PC-deficient mice challenged in septic/endotoxemic models exhibit phenotypes that include hypotension, disseminated intravascular coagulation, elevated inflammatory mediators, neutrophil adhesion to the microvascular endothelium, and loss of protective endothelial and epithelial cell barriers. Further, inflammatory bowel disease has been correlated with diminished endothelial PC receptor and thrombomodulin levels in the intestinal mucosa. Downregulated expression of the cofactor, protein S, as well as PC, is also associated with ischemic stroke. Studies to elucidate further the structural elements that differentiate the various functions of PC will serve to identify novel therapeutic approaches toward regulating these and other diseases.
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PMID:The protein C pathway and pathologic processes. 1963 Jul 87

TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Neutralizing anti-mouse TL1A Ab attenuates chronic colitis in two T-cell driven murine models, suggesting that TL1A is a central modulator of gut mucosal inflammation in inflammatory bowel disease. We showed previously that TL1A is induced by immune complexes via the Fc gamma R signaling pathway. In this study, we report that multiple bacteria, including gram negative organisms (E. coli, E. coli Nissle 1917, Salmonella typhimurium), gram positive organisms (Listeria monocytogenes, Staphylococcus epidermidis), partial anaerobes (Campylobacter jejuni), and obligate anaerobes (Bacteroides thetaiotaomicron, Bifidobacterium breve, Clostridium A4) activate TL1A expression in human APC, including monocytes and monocyte-derived DC. Bacterially induced TL1A mRNA expression correlates with the detection of TL1A protein levels. TL1A induced by bacteria is mediated in part by the TLR signaling pathway and inhibited by downstream blockade of p38 MAPK and NF-kappaB activation. Microbial induction of TL1A production by human APC potentiated CD4(+) T-cell effector function by augmenting IFN-gamma production. Our findings suggest a role for TL1A in pro-inflammatory APC-T cell interactions and implicate TL1A in host responses to enteric microorganisms.
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PMID:Microbial induction of inflammatory bowel disease associated gene TL1A (TNFSF15) in antigen presenting cells. 1983 6

IL-33 is a novel multi-functional IL-1 family member that, in contrast to other family members, is associated with Th2 responses. IL-33 signals via a heterodimer composed of its receptor, IL-1 receptor-like-1 (IL-1RL1), more commonly known as ST2L, and the IL-1R accessory protein. ST2L is expressed by endothelial cells, mast cells, basophils, Th2 cells, and DC. IL-33 has been associated with several immune-mediated disorders, including asthma, arthritis, and inflammatory bowel disease. In contrast, there is evidence that IL-33 can inhibit atherosclerosis development. A report in this issue of the European Journal of Immunology reveals a novel function of IL-33: the ability to promote myeloid DC generation in murine BM cell cultures, by triggering GM-CSF production by other BM cells, likely basophils. DC generated in the presence of IL-33 are maturation resistant, with only minimal T-cell stimulatory ability, associated with comparatively high levels of programmed death receptor ligand expression. This commentary discusses several questions raised by these findings, and provides a basis for further evaluation of IL-33 and ST2L in regulation of APC generation and function in both innate and adaptive immunity.
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PMID:IL-33 broadens its repertoire to affect DC. 1975 Apr 79

Thrombosis is a well recognized complication of inflammatory bowel disease that occurs in 1.3 to 6.4% of patients, however, cerebral vascular involvement is unusual. We present the case of a 16-year-old female in whom cerebral venous thrombosis was the presenting symptom of an active ulcerative pancolitis. Thrombophilia screen (plasma levels of proteins C and S, antithrombin, antibeta2-glycoprotein, lupus anticoagulant and anticardiolipin antibodies, activated protein C resistance, homocystein level antinuclear antibodies) was negative. The patient was successfully treated with anticoagulant therapy, phenobarbital and sulfasalazine. Cerebral venous thrombosis is an exceptional presenting feature of ulcerative colitis. Disease activity may play a major role in the occurrence of thrombosis.
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PMID:Cerebral venous sinus thrombosis as presenting feature of ulcerative colitis. 1990 70


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