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)

The aim of the study was to discover if soluble tumour necrosis factor receptors (sTNF-R p55 and p75) in the urine of patients with inflammatory bowel disease (IBD) could be used to monitor the different stages of the activity of the diseases. Twenty five patients with either Crohn's disease or ulcerative colitis were followed up during a longterm study. The 16 patients who become acutely ill with either Crohn's disease or ulcerative colitis had significantly higher concentrations of sTNF-R p55 and p75 in their urine compared with those who were in remission, or those who were normal controls. There was a significant correlation between increased concentrations (> 20 ng/ml) of both sTNF-R p55 and p75 in the urine and a high Crohn's disease activity index (CDAI) and colitis activity index (CAI). Therefore, determination of sTNF-R is a good non-invasive parameter that can be used to assess the activity of disease and the efficacy of treatment.
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PMID:Soluble tumour necrosis factor receptors p55 and p75 in the urine monitor disease activity and the efficacy of treatment of inflammatory bowel disease. 856 47

Tumor necrosis factor (TNF) is a cytokine produced by macrophages and T lymphocytes that acts through two distinct receptors, TNFR1 (60 kD, CD120a) and TNFR2 (80 kD, CD120b), to affect cellular proliferation, differentiation, survival, and cell death. In addition to its proinflammatory actions in mucosal tissue, TNF is important for liver regeneration. Keratin 8 (K8) and keratin 18 (K18) form intermediate filaments characteristic of liver and other single cell layered, internal epithelia and their derivative cancers. K8-deficient (K8(-)) mice, which escape embryonic lethality, develop inflammatory colorectal hyperplasia, mild liver abnormalities, and tolerate hepatectomy poorly. We show that normal and malignant epithelial cells deficient in K8 and K18 are approximately 100 times more sensitive to TNF-induced death. K8 and K18 both bind the cytoplasmic domain of TNFR2 and moderate TNF-induced, Jun NH(2)-terminal kinase (JNK) intracellular signaling and NFkappaB activation. Furthermore, K8(-) and K18(-) mice are much more sensitive to TNF dependent, apoptotic liver damage induced by the injection of concanavalin A. This moderation of the effects of TNF may be the fundamental function of K8 and K18 common to liver regeneration, inflammatory bowel disease, hepatotoxin sensitivity, and the diagnostic, persistent expression of these keratins in many carcinomas.
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PMID:Keratin-dependent, epithelial resistance to tumor necrosis factor-induced apoptosis. 1074 83

Cardiac disease in association with inflammatory bowel disease (IBD) is uncommon. Reports include pericarditis, pericardial effusion, myocarditis, myocardial infarction, endocarditis and arrythmias. Myocardial inflammation related to IBD may be due to a drug hypersensitivity reaction or micronutrient deficiency, or may be secondary to the underlying IBD as an extraintestinal manifestation. In this setting, myocarditis usually presents as congestive heart failure and/or refractory arrhythmia. Prognosis varies among reported cases, including complete recovery, remission with recurrence and fatal disease. Treatment of myocarditis has included aminosalicylates and immunosuppressive medications. Recently, newer therapies for IBD have been developed, such as tumour necrosis factor-alpha (TNF-a) antagonists. The present report describes a case of a 46-year-old man with clinical and endoscopic evidence of moderately active colonic Crohn's disease who developed congestive heart failure due to giant cell myocarditis. Little clinical improvement occurred with immunosuppressive therapy. Only after the addition of etanercept, a TNF-a p75 receptor antagonist, did complete clinical resolution occur. These authors conclude that the use of TNF-a antagonists may be considered in the treatment of life-threatening extraintestinal manifestations of inflammatory bowel disease.
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PMID:Giant cell myocarditis, in a patient with Crohn's disease, treated with etanercept--a tumour necrosis factor-alpha antagonist. 1157 4

Many studies have indicated changes in neuropeptides in inflammatory bowel disease (IBD), but with contradictory results. Nerve growth factor also has a potential role in the maintenance of enteric nerves and may be associated with IBD. A quantitative immunohistochemical method was used to measure area density of immunoreactive nerves in the colonic mucosa of surgical specimens. No significant differences in immunoreactivity for substance P, vasoactive intestinal polypeptide, growth associated protein 43, and the neurotrophin receptor p75 were seen in the control, Crohn's, and ulcerative colitis groups. Compared to age-matched normal colon (N = 18), there was an increase in neutrophil number in Crohn's (P < 0.05) and ulcerative colitis (P < 0.01) (both N = 9). There were positive correlations (P < 0.05) between neutrophil number and growth associated protein, between p75 and substance P immunoreactive nerves in ulcerative colitis, and between p75 and vasoactive intestinal polypeptide in Crohn's specimens. These data indicate a link between the immunologic and nervous systems in IBD.
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PMID:Neuropeptides and nerve growth in inflammatory bowel diseases: a quantitative immunohistochemical study. 1191 10

As a result of extensive clinical and basic research, the pivotal role of tumour necrosis factor (TNF) in the pathogenesis of chronic inflammatory diseases such as inflammatory bowel disease (IBD) has now generally been acknowledged. This has led to promising clinically effective anti-TNF-strategies. Of note, there is more and more evidence that TNF seems to play a key role in other gastrointestinal diseases including Helicobacter pylori infection, pancreatitis, viral hepatitis and toxic liver damage, too. The action of TNF at the cellular level is mediated by two cell surface receptors, TNF-R1 (p60) and TNF-R2 (p80). The function of these receptors and the downstream intracellular signal transduction pathway have been extensively studied in vitro and it can be expected, that there are critically important steps in TNF-signal transduction that might be dysregulated in these disease states. Their elucidation could lead to a better understanding of the pathogenesis of these diseases, in particular IBD and potentially reveal new, more specific therapeutic targets. Objective of this review is to give an overview about the current knowledge on TNF signal transduction in relationship to selected examples of important gastrointestinal disorders with special focus on IBD. Finally, the implications for future research efforts will be discussed.
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PMID:Functional relevance of soluble TNF-alpha, transmembrane TNF-alpha and TNF-signal transduction in gastrointestinal diseases with special reference to inflammatory bowel diseases. 1229 83

The therapy of chronic inflammatory diseases like rheumatoid arthritis (RA) and inflammatory bowel disease (IBD) has recently been enriched by the successful launch of the anti-cytokine biologicals Etanercept (tumor necrosis factor (TNF) receptor-p75 Fc fusion protein), Infliximab (chimeric anti-human TNF-alpha monoclonal antibody), Adalimumab (recombinant human anti-human TNF-alpha monoclonal antibody) and Anakinra (recombinant form of human interleukin 1beta (IL-1) receptor antagonist). The success of these novel treatments has impressively demonstrated the clinical benefit that can be gained from therapeutic intervention in cytokine signalling, highlighting the central role of proinflammatory cytokine systems like IL-1alpha and TNF-alpha to be validated targets. However, all of the anti-cytokine biologicals available to date are proteins, and therefore suffering to a varying degree from the general disadvantages associated with protein drugs. Therefore, small molecular, orally active anti-cytokine agents, which target specific pathways of proinflammatory cytokines, would offer an attractive alternative to anti-cytokine biologicals. A number of molecular targets have been identified for the development of such small molecular agents but p38 mitogen-activated protein (MAP) kinase occupies a central role in the regulation of IL-1beta and TNF-alpha signalling network at both the transcriptional and translational level. Since the mid-1990s, an immense number of inhibitors of p38 MAP kinase has been characterised in vitro, and to date several compounds have been advanced into clinical trials. This review will highlight the correlation between effective inhibition of p38 MAP kinase at the molecular target and cellular activity in functional assays of cytokine, particularly TNF-alpha and IL-1beta production. SAR will be discussed regarding activity at the enzyme target, but also with regard to properties required for efficient in vitro and in vivo activity.
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PMID:New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase. 1645 63

Steroids are the best known anti-inflammatory drugs and have been in use for more than 50 years. Their chronic use however was limited by safety concerns. Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 inhibitors although devoid of steroid side effects often possess gastrointestinal side effects. In addition recent data suggest that chronic use of some Cox inhibitors is associated with cardiovascular risk. Currently biologics represent the best option for many inflammatory diseases where TNFalpha is the main culprit. These include rheumatoid arthritis, ulcerative colitis, inflammatory bowel disease and psoriasis. A wealth of information is now available on the role of different cytokines and adhesion molecules in the origin and progression of inflammatory diseases. With the success of protein therapeutics such as Etanercept (Enbrel), which binds TNFalpha and inhibits its activity, research has been focused on developing small peptides that can interfere with cytokines or specific cell surface molecules and inhibit the inflammatory reactions. Here we review these peptides that are in discovery and development phases and their potential in the treatment of inflammatory diseases.
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PMID:Emerging peptide therapeutics for inflammatory diseases. 1691 1

Tumor necrosis factor-alpha (TNF) is a major mediator of apoptosis as well as immunity and inflammation. Inappropriate production of TNF or sustained activation of TNF signaling has been implicated in the pathogenesis of a wide spectrum of human diseases, including cancer, osteoporosis, sepsis, diabetes, and autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TNF binds to two specific receptors, TNF-receptor type I (TNF-R1, CD120a, p55/60) and TNF-receptor type II (TNF-R2, CD120b, p75/80). Signaling through TNF-R1 is extremely complex, leading to both cell death and survival signals. Many findings suggest an important role of phosphorylation of the TNF-R1 by number of protein kinases. Role of TNF-R2 phosphorylation on its signaling properties is understood less than TNF-R1. Other cellular substrates as TRADD adaptor protein, TRAF protein family and RIP kinases are reviewed in relation to TNF receptor-mediated apoptosis or survival pathways and regulation of their actions by phosphorylation.
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PMID:TNF signaling: early events and phosphorylation. 1806 42

Abstract Rats transgenic for HLA-B27 and human beta2microglobulin (B27TR) develop a multi-systemic disease resembling inflammatory bowel disease (IBD) and spondyloarthritis. TNFalpha has a crucial role in chronic inflammation. Our objective was to evaluate the effect of anti-TNFalpha treatment on spontaneous IBD in B27TR. Nine-week-old B27TR received monoclonal anti-TNFalpha or an isotypic IgG2a,k up to age of 18 weeks. A second group was monitored up to 18 weeks and then randomly assigned to anti-TNFalpha or IgG2 a,k treatment. Each rat was monitored for clinical IBD manifestations. After sacrifice, the colon was examined for pathological changes. TNFalpha receptors (TNF-R1, TNF-R2), Fas/Fas-L expression and apoptosis were evaluated. IgG2a,k-treated and untreated B27TR presented signs of IBD at 11 weeks, whereas in anti-TNFalpha-treated B27TR no IBD signs were detected. In the late treatment, IBD signs improved after 1 week. Histopathological analysis of IgG2a,k-treated B27TR colon showed inflammatory signs that were widely prevented by early anti-TNFalpha treatment. Late treatment did not significantly reduce inflammation. TNF-R1 was weakly expressed in intestinal epithelial cells of IgG2a,k-treated B27TR, while it was comparable to controls in anti-TNFalpha-treated animals. TNF-R2 immunopositivity was strongly evident in IgG2a,k-treated B27TR, whereas was absent in anti-TNFalpha-treated rats. RT-PCR confirmed these results. IgG2a,k-treated B27TR showed, at 18 weeks, few Fas-positive cells and an increase of Fas-L-positive cells. At 27 weeks, Fas-/Fas-L-positive cell number was significantly low. Anti-TNFalpha treatment increased Fas-L expression, whereas Fas increased only with the early treatment. TNFalpha blockade is effective in preventing inflammation in early phase of IBD, maintaining the homeostatic balance of apoptosis.
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PMID:TNFalpha blockade prevents the development of inflammatory bowel disease in HLA-B27 transgenic rats. 1836 45

Tumor necrosis factor-alpha (TNF-alpha) was first isolated two decades ago as a macrophageproduced protein that can effectively kill tumor cells. TNF-alpha is also an essential component of the immune system and is required for hematopoiesis, for protection from bacterial infection and for immune cell-mediated cytotoxicity. Extensive research, however, has revealed that TNF-alpha is one of the major players in tumor initiation, proliferation, invasion, angiogenesis and metastasis. The proinflammatory activities link TNF-alpha with a wide variety of autoimmune diseases, including psoriasis, inflammatory bowel disease, rheumatoid arthritis, systemic sclerosis, systemic lupus erythematosus, multiple sclerosis, diabetes and ankylosing spondylitis. Systemic inhibitors of TNF such as etanercept (Enbrel) (a soluble TNF receptor) and infliximab (Remicade) and adalimumab (Humira) (anti-TNF antibodies) have been approved for the treatment inflammatory bowel disease, psoriasis and rheumatoid arthritis. These drugs, however, exhibit severe side effects and are expensive. Hence orally active blockers of TNF-alpha that are safe, efficacious and inexpensive are urgently needed. Numerous products from fruits, vegetable and traditional medicinal plants have been described which can suppress TNF expression and TNF signaling but their clinical potential is yet uncertain.
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PMID:Targeting TNF for Treatment of Cancer and Autoimmunity. 1976 65


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