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)

Cytokines play an important role in the pathology of inflammatory bowel disease by determining the nature of the mucosal immune response. One way of establishing whether CD and UC are causally related to a defect in the host immune response is to look for polymorphisms that are over-represented in these populations. This is being carried out at great pace both for the cytokine genes and for some other immune response genes. A number of gene expression studies have established that those cytokines produced by activated macrophages such as IL-1, IL-6 and TNF are significantly elevated in both diseases. Differences between the two diseases are less clear, and, where they have been found, they probably reflect the accuracy and sensitivity of quantification. The picture is less clear for the T-cell-derived cytokines, which are generally expressed at a lower copy number in intestinal tissue compared to the monokines. For Crohn's disease, the TH1 cytokines IL-2 and IFN may be abnormally elevated or decreased. In contrast, the TH1/TH2 profile in UC is not significantly different from normal controls. Further work is required to confirm these findings.
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PMID:Cytokines and inflammatory bowel disease. 873 6

If one reviews the literature with zeal, it is increasingly apparent that few organs escape recruitment when IBD is chronic or progressive. Insights into mucosal pathophysiology have helped with understanding the more frequent extraintestinal manifestations, but the mechanisms attendant to the development of less common events (e.g. acute pancreatitis, concurrent gluten sensitive enteropathy, or active pulmonary disease) remain either poorly studied or obscure. It is particularly interesting, however, to read reports of abnormal pulmonary function, generally of the obstructive type, correlated to measurements of abnormal intestinal permeability in patients with either active pulmonary sarcoid or pulmonary involvement in Crohn's disease. It has been further speculated that similarities in the mucosal immune system of the lung and intestine are responsible for evidence of bronchial hyperreactivity in patients with active IBD. Finally, it is important to recognize that extensions of the inflammatory process are not restricted to the development of organ-based events but may be responsible for some of the most frequent systemic abnormalities detected in IBD patients. It is now also well confirmed that the cytokine environment in IBD can support activated coagulation and, in some clinical situations, overt vascular thrombosis. The cerebrovascular complications of IBD are well recognized and range from peripheral venous thrombosis to central stroke syndromes and pseudotumor cerebri. Reports of focal white matter lesions in the brains of patients with IBD or an increased incidence of polyneuropathy may be other clinical examples of regional microvascular clotting. Microvascular injury appears to be more ubiquitously present, with reports ranging from a speculated primary causative role (e.g., granulomatous vasculitis in the mesenteric circulation) to the utility of nailbed vasospasm, in Crohn's disease, as a clinical marker for disease activity. It is also reported that IL-6 suppression of erythropoietin production is a major feature of the chronic anemia seen in active IBD. Moreover, the capacity of peripheral monocytes from active IBD patients to secrete TNF and IL-8 is reported predictive for the degree of therapeutic response from recombinant erythropoietin. These collected observations constitute another excellent example of the symmetry between basic science and clinical utility. It is from the context of applied basic science that many future therapies will arise. Empiricism will lose much of its appeal as clinical observations will be increasingly translated into cellular language. Already in animal models, elemental diets diminish IL-6-related acute inflammatory injury, and reductions in dietary lipid alter the antigenicity of bacteria. Provocatively, in humans, unconfirmed reports have even associated diet therapy with the resolution of uveitis and pyoderma gangrenosum. It is likely that efforts will also be made to induce oral tolerance if specific triggering proteins are discovered or to alter bowel flora if such an arcane area of investigation becomes resurgent.
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PMID:Extraintestinal considerations in inflammatory bowel disease. 880 40

The inflammatory bowel diseases frequently require surgery because of intestinal complications. Animal models of inflammatory bowel disease, in particular those that histopathologically resemble Crohn's disease, are characterized by increased mucosal TNF production, and anti-TNF antibodies have shown efficacy in decreasing disease activity. These data have provided a rationale for immunotheraphy of Crohn's disease. Administration of anti-TNF antibodies to patients with Crohn's disease not responding to standard immunosuppressive treatment rapidly induced complete remissions, and healing of intestinal ulceration. A rapid reduction of circulating IL-6, CPR, and sPLA2 levels was observed in all patients, as well as a reduction of mucosal cells expressing RANTES and MIP-1. Short-term treatment with anti-TNF antibodies was not associated with significant toxicity, but results from long-term administration are still lacking. These data indicate that TNF is a pivotal and central inflammatory mediator in this disease. Further characterization of the precise mechanism of action of anti-TNF antibody therapy may further unravel the cause of immune dysregulation in Crohn's disease.
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PMID:Tumor necrosis factor (TNF) in inflammatory bowel disease: gene polymorphisms, animal models, and potential for anti-TNF therapy. 891 36

Mice with targeted deletion of the G protein G(alpha)i2 develop an inflammatory bowel disease closely resembling ulcerative colitis. To better define disease pathogenesis, the mucosal immune system in G(alpha)i2-deficient mice was studied. Phenotypic analysis of large intestine lamina propria lymphocytes revealed a large increase in memory CD4+ T cells (CD44high, CD45RBlow, CD62Llow). Furthermore, expression of the mucosal homing receptor integrin beta7 was increased on mucosal, but not systemic, CD4+ T cells. Analysis of cytokine production revealed a marked increase in proinflammatory Th1-type cytokines in inflamed colons, as compared with wild-type mice or G(alpha)i2-deficient mice without colitis. Thus, IFN-gamma and IL-1beta levels were increased 13-fold and 30-fold, respectively, with more modest increases in IL-6 levels (5-fold) and TNF levels (2-fold). Inflamed colons of G(alpha)i2-deficient mice also demonstrated increased IL-12 p40 mRNA levels. No increase in IL-2, IL-4, IL-5, and IL-10 was seen. Large intestinal epithelial cells in G(alpha)i2-deficient mice with colitis were found by immunohistochemistry to express increased levels of both MHC class I and class II Ags. Colitis was associated with increased IgG levels (60-fold increase), predominantly IgG2a (135-fold increase), in large but not small intestinal secretions. This was shown by ELISPOT analysis to result from local production within the lamina propria.
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PMID:G(alpha)i2-deficient mice with colitis exhibit a local increase in memory CD4+ T cells and proinflammatory Th1-type cytokines. 901 44

The cytokines TNF and IL-1 have been implicated as mediators of the inflammatory processes in patients with inflammatory bowel disease (IBD). To investigate the role of these cytokines in mucosal inflammation we used anti-cytokine strategies in a mouse model of acute and chronic colitis. Mice which received 5% dextran sulphate sodium (DSS) in their drinking water showed signs of acute colitis on day 4, with severe weight loss and bloody diarrhoea. Chronic colitis was established after four cycles of feeding 5% DSS for 7 days and water for 10 days, with the mice showing diarrhoea but no weight loss. In acute colitis, treatment with anti-IL-1 reagents, anti-TNF MoAb, or dexamethasone (DEX) led to aggravation. By contrast, in chronic colitis, treatment of mice with several IL-1 activity-inhibiting reagents failed to show significant effects, whereas anti-TNF MoAb or DEX significantly reduced the colitis. We conclude that in acute colitis IL-1 and TNF are beneficial, whereas in chronic colitis, TNF but not IL-1 seems to play a major role in perpetuation of chronic inflammation.
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PMID:Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. 903 Aug 75

The mechanisms underlying inflammatory bowel disease (IBD) remain obscure but the importance of inflammatory processes is clear and most pharmacological therapies inhibit inflammation. The search for more effective agents with low toxicity continues. To test the possibility that the antiinflammatory/anticytokine peptide alpha-MSH can be used to control IBD, the peptide was administered to a murine colitis model. The peptide treatment had marked salutary effects: it reduced the appearance of fecal blood by over 80%, inhibited weight loss, and prevented disintegration of the general condition of the animals. Mice given alpha-MSH showed markedly lower production of TNF alpha by tissues of the lower colon stimulated with concanavalin A; the inhibitory effect of alpha-MSH on production of inflammatory nitric oxide by lower bowel tissue was even greater. The combined results indicate that alpha-MSH modulates experimental IBD, perhaps by inhibiting production within the gut of the local proinflammatory agents TNF alpha and nitric oxide, or by inhibiting inflammatory processes closely linked to these mediators.
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PMID:alpha-MSH modulates experimental inflammatory bowel disease. 914 24

Animal models of inflammatory bowel disease have provided insight in the regulation of mucosal inflammation. This has resulted in novel therapeutic approaches that specifically target a single inflammatory mediator. Monoclonal antibody therapy has been used in steroid refractory Crohn's disease patients. Anti-TNF antibody administration induced complete remissions and few side effects were observed. Although these findings need to be confirmed in controlled and long term treatment studies they may guide the development of specific and effective therapies for these diseases.
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PMID:Monoclonal antibody therapy of inflammatory bowel disease. 915 42

In the past few years new concepts have been formulated for the therapeutic management of difficult-to-treat inflammatory bowel disease, based on better insights in the pathophysiological processes in inflamed colonic mucosa. TNF alpha, for example, has been shown to play a major role orchestrating several other cytokines and pathways in the immunological network. TNF alpha is a pro-inflammatory cytokine. In contrast, IL-10 is an anti-inflammatory cytokine. IL-10-deficient mice ('IL-10 knockout mice') will spontaneously develop enteritis in several parts of the digestive tract. Administration of IL-10 has been shown to improve and even to prevent the enteritis in these mice. One of the functions of IL-10 is to inhibit the TNF alpha production. Elimination of TNF alpha with anti-TNF alpha antibodies and administration of IL-10 is, therefore, thought to achieve healing of the inflamed mucosa in man as well. The first uncontrolled studies with intravenous administration of chimeric anti-TNF alpha antibodies and with human recombinant IL-10 are hopeful for the future management of patients with inflammatory bowel disease; particularly since a fast healing of colonic mucosa was demonstrated and no serious adverse events were described. One has to be aware, however, of allergic reactions to the 'foreign' peptide. Because of rapid fibrosing and scarring in a narrow lumen, e.g. the ileum, stenosis formation could take place. In one described case a surgical intervention was needed because of this complication. For the near future these new and potent drugs seem very promising, although at present they are only available for trials with Crohn's disease patients. Certainly, in the coming years more immunomodulating drugs will be developed for use in man.
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PMID:New therapies for inflammatory bowel disease: an update on chimeric anti-TNF alpha antibodies and IL-10 therapy. 920 Mar 15

Mast cells can serve as a possible important source of cytokine production in inflamed tissue which can be regulated by stimuli different from those activating other immune system cells. To study the expression of specific genes in mast cells derived from small human colonic mucosal endoscopic biopsies, we first modified a previously reported procedure to achieve a significantly enriched mast cell fraction. Then, by using single-cell RT-PCR analysis the expression of the IgE Fc receptor (Fc epsilonRI) and c-kit mRNA was determined. It was observed that the Fc epsilonRI-positive cells also expressed c-kit. This observation provided further evidence that Fc epsilonRI-positive cells are indeed mast cells. Analysis of biopsies from 12 patients (four control and eight patients with inflammatory bowel disease (IBD)) was carried out, revealing that all of the Fc epsilonRI-positive cells expressed IL-3, while the expression of IL-4 was detected only in some of these positive cells. TNF alpha was not detected in these cells. Therefore, it would seem that most intestinal mast cells produce IL-3. Since it has been reported that IL-3 synthesis was down-regulated in steroid-treated cells, the expression pattern of IL-3 in intestinal mast cells derived from steroid-treated IBD patients was then determined. IL-3 mRNA was detected in only two out of 24 Fc epsilonRI-positive cells derived from these steroid-treated patients. These results lend strong support to the idea that the down-regulation of IL-3 in mast cells derived from steroid-treated IBD patients occurs in vivo and could be an important mechanism for immunomodulation in IBD.
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PMID:Analysis of cytokine profile in human colonic mucosal Fc epsilonRI-positive cells by single cell PCR: inhibition of IL-3 expression in steroid-treated IBD patients. 930 51

The production of pro-inflammatory cytokines, such as interleukins 1 and 6 and tumour necrosis factors, occurs rapidly following trauma or invasion of the body by pathogenic organisms. The cytokines mediate the wide range of symptoms associated with trauma and infection, such as fever, anorexia, tissue wasting, acute phase protein production and immunomodulation. In part, the symptoms result from a co-ordinated response, in which the immune system is activated and nutrients released, from endogenous sources, to provide substrate for the immune system. Although the cytokine mediated response is an essential part of the response to trauma and infection, excessive production of pro-inflammatory cytokines, or production of cytokines in the wrong biological context, are associated with mortality and pathology in a wide range of diseases, such as malaria, sepsis, rheumatoid arthritis, inflammatory bowel disease, cancer and AIDS. Cytokine biology can be modulated by antiinflammatory drugs, recombinant cytokine receptor antagonists and nutrients. Among the nutrients, fats have a large potential for modulating cytokine biology. A number of trials have demonstrated the anti-inflammatory effects of fish oils, which are rich in n-3 polyunsaturated fatty acids, in rheumatoid arthritis, inflammatory bowel disease, psoriasis and asthma. Animal studies, conducted by ourselves and others, indicate that a range of fats can modulate pro-inflammatory cytokine production and actions. In summary fats rich in n-6 polyunsaturated fatty acids enhance IL1 production and tissue responsiveness to cytokines, fats rich in n-3 polyunsaturated fatty acids have the opposite effect, monounsaturated fatty acids decrease tissue responsiveness to cytokines and IL6 production is enhanced by total unsaturated fatty acid intake. There are a large number of potential cellular mechanisms which may mediate the effects observed. The majority relate to the ability of fats to alter the composition of membrane phospholipids. As a consequence of alterations in phospholipid composition, membrane fluidity may change, altering binding of cytokines to receptors and G protein activity. The nature of substrate for various signalling pathways associated with cytokine production and actions may also be changed. Consequently, alterations in eicosanoid production and activation of protein kinase C may occur. We have examined a number of these potential mechanisms in peritoneal macrophages of rats fed fats with a wide range of fatty acid composition. We have found that the total C18:2 and 20:4 diacyl species of phosphatidylethanolamine in peritoneal macrophages relates in a positive curvilinear fashion with dietary linoleic acid intake; that TNF induced IL1 and IL6 production relate in a positive curvilinear fashion to linoleic acid intake; that leukotriene B4 production relates positively with dietary linoleic acid intake over a range of moderate intakes and is suppressed at high intakes, while PGE2 production is enhanced. There was no clear relationship between linoleic acid intake and membrane fluidity, however fluidity was influenced in a complex manner by the type of fat in the diet, the period over which the fat was fed and the presence of absence of TNF stimulation. None of the proposed mechanisms, acting alone, can explain the positive effect of dietary linoleic acid intake on pro-inflammatory cytokine production. However each may be involved, in part, in the modulatory effects observed.
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PMID:Modulation of pro-inflammatory cytokine biology by unsaturated fatty acids. 955 30


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