Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: HUMANGGP:017444 (TNF)
 61,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal immune response with elevated levels of the Th1 cytokines TNF, IL-12 and IFN-gamma. The luminal flora has been implicated as a major factor contributing to the initiation and perpetuation of chronic intestinal inflammation by as yet unknown mechanisms. Bacterial DNA contains unmethylated cytosine-guanosine dinucleotides (CpG) which strongly activate Th1-mediated immune responses. To test whether these CpG-motifs contribute to intestinal inflammation we treated mice with dextran-sulfate-sodium (DSS)-induced acute or chronic colitis for 5 days with CpG-containing oligodeoxynucleotides (CpG-ODN). Colonic inflammation was assessed by histological scoring. Colonic cytokine RNA was quantified by reverse transcription-PCR and cytokine secretion from mesenterial lymph node cells by ELISA. In chronic colitis, CpG-ODN treatment severely aggravated inflammation by 50%. Colonic expression of IFN-gamma and TNF was elevated (200- and 150-fold, respectively) and IFN-gamma and IL-12 secretion from lymph node cells was increased 5,000- and 8-fold, respectively, compared to GpG-ODN-treated controls. Similar effects were obtained in acute colitis. In conclusion, CpG-motifs of bacterial DNA have proinflammatory activity by strengthening the Th1 arm of immunity in DSS-induced colitis, and might therefore play a significant role in the initiation and perpetuation of inflammation in IBD.
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PMID:CpG motifs of bacterial DNA exacerbate colitis of dextran sulfate sodium-treated mice. 1211 30

Deregulated TNF production, be it low or high, characterizes many autoimmune diseases. Recent evidence supports a dualistic, pro-inflammatory and immune- or disease-suppressive role for TNF in these conditions. Blocking TNF in autoimmune-prone chronic inflammatory diseases may, therefore, lead to unpredictable outcomes, depending on timing and duration of treatment. Indeed, blockade of TNF in human rheumatoid arthritis or inflammatory bowel disease patients, although so far impressively beneficial for the majority of patients, it has also led to a significant incidence of drug induced anti-dsDNA production or even in manifestations of lupus and neuro-inflammatory disease. Notably, anti-TNF treatment of multiple sclerosis patients has led almost exclusively to immune activation and disease exacerbation. We discuss here recent evidence in murine disease models, indicating an heterogeneity of TNF receptor usage in autoimmune suppression versus inflammatory tissue damage, and put forward a rationale for a predictably beneficial effect of 'anti-TNFR' instead of 'anti-TNF' treatment in human chronic inflammatory and autoimmune conditions.
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PMID:Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments. 1222 May 46

Growth failure (GF) is one of the major complications affecting children with inflammatory bowel disease. The faltering is temporary in 40-50% of cases and prolonged in 10-20% in Crohn's disease (CD). Such failure is rare in children with ulcerative colitis (5%). This complication is often associated with retarded bone development and delayed onset of sexual maturation. The delayed linear growth has a variety of causes including insufficient intake due to anorexia and the inflammatory process with increased energy and protein expenditure. Other factors are increased intestinal loss, secondary hypopituitarism and treatment with steroids. Therapeutic strategies of CD in children have changed this last decade by introducing new therapeutic agents such as topic steroids, immunosuppressors, anti-TNF (antibody and notably in children enteral nutrition which has shown its efficacy in inducing remissions of active CD, restoring nutritional status and stimulation of linear growth. The results of a recent prospective multicentric study over 2 years in 82 CD show that severe GF (-2 SD) is initially present in 15% (n = 12), among them 11 remain < -2SD after 2 years of follow-up. Six patients who were on the normal range initially increased their GF during the follow-up (< -2SD) (total 21% < -2SD (n = 17) at 2 years). At inclusion in this group there was no difference in growth velocity, used of steroids, enteral nutrition or severity of CD as compared to the group with no GF. It suggests that new treatment strategy should be developed in the future for this specific complication of paediatric CD.
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PMID:Growth in paediatric Crohn's disease. 1237 7

The key role and contribution of various pro-inflammatory cytokines in common chronic inflammatory disorders such as inflammatory bowel disease (IBD) has been thoroughly investigated in recent years. Besides IL-1, TNF-alpha has been identified as one of the central immune mediators controlling inflammatory processes. Not surprisingly, neutralisation of these cytokines has been introduced into clinical research. Crohn's disease (CD) is one of the chronic inflammatory disorders where TNF-alpha seems to have a particularly important role. Neutralisation of this cytokine by specific antibodies, for example infliximab, has been shown recently to affect the clinical phenotype of this disorder. Other TNF-neutralising approaches such as etanercept have also been studied in patients with CD but with less successful outcomes. These new cytokine-targeting approaches have changed clinical medicine in the field of inflammatory disorders.
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PMID:Antitumour necrosis factor therapy in Crohn's disease. 1238 70

The relatively recent development of genetically engineered agents has the potential to alter the treatment of Crohn's disease radically, and drugs that inhibit tumor necrosis factor-alpha (TNFalpha) have been introduced as a new therapeutic class with high efficacy, rapid onset of action, prolonged effect, and improved tolerance. However these agents are expensive and at least one-third of the eligible patients fail to show any useful response. Finding a means to predict those who will respond, and to anticipate relapse are, therefore, of obvious importance. T helper-type 1 (Th1) lymphocytes orchestrate much of the inflammation in Crohn's disease mainly via production of TNFalpha, which appears to play a pivotal role as a pro-inflammatory cytokine. It exerts its effects through its own family of receptors (TNFR1 and TNFR2), the end results of which include apoptosis, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activation and NF-kappaB activation. Activated NF-kappaB enters the nucleus and induces transcription of genes associated with inflammation, host defense and cell survival. The promoter region of the TNF gene lies between nucleotides -1 and -1300, and encompasses numerous polymorphic sites associated with potential binding sites for various transcription factors. Carriers of the TNF allele 2 (TNF2), which contains a single base-pair polymorphism at the -308 promoter position, produce slightly more TNFalpha in their intestinal mucosa than non-TNF2 carriers. TNF polymorphisms also appear to influence the nature and frequency of extraintestinal manifestations of inflammatory bowel disease (IBD). A number of routes of inhibition of TNF are being investigated. Most extensively evaluated is the use of monoclonal antibodies against TNFalpha (e.g. infliximab). Several large controlled trials indicate that infliximab has a role in treating patients with moderate to severely active Crohn's disease and in fistulating Crohn's disease. Although it would be useful to genetically differentiate 'responders' from 'non-responders,' currently there are few published data on TNF polymorphisms in IBD, and often only selected polymorphisms are genotyped. Small studies have shown possible associations between poor response to infliximab and increasing mucosal levels of activated NF-kappaB, homozygosity for the polymorphism in exon 6 of TNFR2 (genotype Arg196Arg), positivity for perinuclear antineutrophil cytoplasmic antibodies (ANCA), and with the presence of increased numbers of activated lamina propia mononuclear cells producing interferon-gamma and TNFalpha. This is a rapidly changing field, and more information of greater direct clinical benefit can be expected soon.
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PMID:Pharmacogenomics of response to anti-tumor necrosis factor therapy in patients with Crohn's disease. 1242 Oct 92

Cytokine unbalance is responsible for the pathogenesis of diverse inflammatory, autoimmune and infectious diseases, and Tumor Necrosis Factor Alpha (TNF alpha), among other cytokines, plays a central role. TNF alpha production can be regulated at the transcriptional, post-transcriptional, and translational levels. Variability in the promoter and coding regions of the TNF alpha gene may modulate the magnitude of its secretory response. Up to date, several single nucleotide polymorphisms (SNPs) have been identified in the human TNF alpha gene promoter. One of these, is a guanine to adenine transition at position -308, that generates the TNF1 and TNF2 alleles, respectively. The TNF2 allele is associated to a high in vitro TNF expression, and it has also been linked to an increased susceptibility and severity, for a variety of illnesses, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, Alzheimer disease and cerebral malaria among others. It is also associated with a higher septic shock susceptibility and mortality. The investigation of polymorphisms within the TNF alpha cluster will be important in understanding the role of TNF alpha regulation in specific diseases.
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PMID:[Tumor necrosis factor alpha genetic polymorphism as a risk factor in disease]. 1243 54

Inflammatory bowel disease (IBD) is associated with mucosal T cell activation and diarrhea. We found that T cell activation with anti-CD3 mAb induces profound diarrhea in mice. Diarrhea was quantified by intestinal weight-to-length (wt/l) ratios, mucosal Na(+)/K(+)-ATPase activity was determined and ion transport changes were measured in Ussing chambers. Anti-CD3 mAb increased jejunal wt/l ratios by more than 50% at 3 hours, returning to base line after 6 hours. Fluid accumulation was significantly reduced in TNF receptor-1 (TNFR-1(-/-)), but not IFN-gamma knockout mice. Anti-CD3 mAb decreased mucosal Na(+)/K(+)-ATPase activity, which was blocked by anti-TNF mAb and occurred to a lesser degree in TNFR-1(-/-) mice. Neither alpha nor beta subunits of Na(+)/K(+)-ATPase decreased in abundance at 3 hours. Intestinal tissue from anti-CD3-treated mice exhibited increased permeability to mannitol at 1 hour and decreases in electroneutral Na(+) absorption, Na(+)-dependent glucose absorption, and cAMP-stimulated anion secretion at 3 hours. Furthermore, enteral fluid accumulation was observed in CFTR(-/-) mice, indicating a minor role of active anion secretion. These data suggest that diarrhea in IBD is due to TNF-mediated malabsorption rather than to secretory processes. T cell activation induces luminal fluid accumulation by increasing mucosal permeability and reducing epithelial Na(+)/K(+)-ATPase activity leading to decreased intestinal Na(+) and water absorption.
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PMID:T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+-ATPase. 1246 79

Apoptosis is one of the most important regulatory mechanisms in immunological homeostasis. Disturbances in the apoptotic pathways lead to autoimmune disease. Crohn's disease is a chronic inflammatory bowel disease of unknown origin, which seems to be mediated by excessive T cell-mediated immunity. Recently, disturbances in apoptotic pathways of lamina propria T lymphocytes of patients with Crohn's disease have been identified. In the uninflamed, normal intestinal mucosa, lamina propria (LP) T cells are susceptible to activation-induced cell death, but these cells show a resistance to apoptosis based on several disturbances compared to controls. Recently, intriguing data were published using cytokine-targeted therapy (anti-IL12, anti-IL6 receptor, anti-TNF). Actually, these medications restored mucosal immunological imbalance by inducing apoptosis of the LP T cells and seemed to be beneficial in models of Crohn's disease. In this review, mechanisms of immunological homeostasis will be discussed. We will also discuss the fascinating new results of cytokine-targeted therapy in animal models of Crohn's disease and the effects of these drugs in patients with Crohn's disease.
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PMID:Treating Crohn's disease by inducing T lymphocyte apoptosis. 1248 56

The evolving medical armamentarium holds promise for more precise and effective therapies for IBD. The experience with anti-TNF therapy, particularly infliximab, illustrates the potential efficacy of therapies targeted at specific mediators or pathways involved in the pathogenesis. Advances in molecular technology have enabled the development of novel and potentially effective targeted therapies. Equally important is the increasing scientific understanding of the pathogenesis of IBD, which will likely improve the ability to stratify disease and to select therapies based on genotypic, immunologic, and phenotypic profiles in the future.
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PMID:Recent developments in inflammatory bowel disease. 1251 Apr 62

gammadelta T cells have previously been shown to play a protective role in various animal models of chronic inflammation (e.g., experimental autoimmune encephalomyelitis, collagen-induced arthritis, and non-obese diabetes). This immunoregulatory potential is exerted by synthesizing various anti-inflammatory cytokines and growth factors (e.g., transforming growth factor-beta). As the normal balance between inflammatory and regulatory cytokines is perturbed in inflammatory bowel disease (IBD) a protective effect of gammadelta T cells seems likely. This notion is supported by our finding of increased mortality of rats with 2,4,6-trinitrobenzene sulfonic acid-induced colitis following gammadelta T cell depletion. In contrast, no effect was observed after depletion of gammadelta T cells in a Crohn's disease animal model with terminal ileitis (TNF(DeltaARE) mice). Therefore, future studies must further define where in the intestinal immune system gammadelta T cells exert their protective function and how this can be used in the treatment of IBD.
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PMID:Role of gamma delta T cells in inflammatory bowel disease. 1257 19


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