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)

Autoimmune diseases have been studied from the perspective of an abnormal immune response in genetically vulnerable hosts. Although the immune response is responsible for the initiation of autoimmune diseases, the effectors of the disease process likely involves cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). These polypeptides induce a wide variety of inflammatory events which contribute to the destruction of tissue and tissue remodeling in several autoimmune diseases. Blocking IL-1 with its naturally occurring receptor antagonist, the IL-1 receptor antagonist reduces the severity of disease in animal models of inflammation and autoimmune processes. Clinical studies with the IL-1 receptor antagonist will define the role for this cytokine in the pathogenesis of autoimmune diseases such as arthritis, inflammatory bowel disease, type I diabetes and vasculitis.
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PMID:Interleukin-1 and tumor necrosis factor: effector cytokines in autoimmune diseases. 132 Sep 50

The polypeptide cytokine interleukin-1 (IL-1) affects nearly every tissue and organ system. IL-1 is the prototype of the pro-inflammatory cytokines in that it induces the expression of a variety of genes and synthesis of several proteins which, in turn, induce acute and chronic inflammatory changes. Most studies on the biology of IL-1 have been carried out in animals, but human subjects have recently been injected with recombinant IL-1 and the results confirm IL-1 as being a mediator of disease as well as host defense. However, overproduction of IL-1 leads to debilitation of normal host functions; therefore, reduction of IL-1 synthesis or blockade of IL-1 activity becomes a target of therapy in many diseases. Agents for reducing the synthesis or antagonizing the effects of IL-1 have been sought, but the naturally occurring IL-1 receptor antagonist (IL-1Ra) has opened new experimental and clinical approaches. The ability of IL-1Ra to block IL-1 receptors without agonist activities has reduced the severity of diseases such as septic shock, lethal sepsis, inflammatory bowel disease, experimental arthritis, and the spontaneous proliferation of human leukemic cells.
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PMID:The role of interleukin-1 in host responses to infectious diseases. 134 62

Whatever initiates inflammation, the final message mediating cellular invasion is chemical. This consideration allows rational development of anti-inflammatory treatments. Two main classes of chemotactic mediator are recognised. Water-soluble peptides, e.g. cytokines derived from macrophages and other cells, play an important integrating part in the early recruitment of neutrophils and mononuclear cells, and in the amplification of immune responses. Lipid-soluble mediators, of which leukotriene B4 is the most highly chemotactic for neutrophils, are important in secondary amplification. In inflammatory bowel disease, we have shown evidence of increased synthesis of cytokines interleukin 1, 6 and 8. These are associated with activation of circulating monocytes in active Crohn's disease, of lamina propria macrophages in relapse of both ulcerative colitis and Crohn's disease, and development of adhesion molecules on vascular endothelium. Our studies show that interleukin 6 is selectively increased in Crohn's disease, whilst preliminary findings suggest that enhanced synthesis of interleukin 8 is particularly characteristic of ulcerative colitis. Patterns of cytokine synthesis may, therefore, be of diagnostic value. They also offer the potential for therapeutic strategies since cytokine antagonists are becoming available. We have also demonstrated increased synthesis of leukotrienes in active inflammatory bowel disease. Since leukotriene B4 is quantitatively the main chemotactic signal in the mucosa in inflammatory bowel disease during relapse, we investigated the therapeutic effect of suppressing leukotriene B4 synthesis by treating patients with fish oil (as Hi-EPA), giving 4.5 g daily of eicosapentaenoic acid. This competes for the 5-lipoxygenase enzymes, inhibiting leukotriene B4 and promoting synthesis of the less chemotactic product, LTB5.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Therapeutic interventions in gastrointestinal disease based on an understanding of inflammatory mediators. 135 43

Proliferation, maturation, chemotaxis, and activation of neutrophils and monocytes are mediated largely by cytokines, including colony-stimulating factors and lymphokines. Cytokines produced in the intestinal mucosa contribute to the increased migration of neutrophils and monocytes into the lesion of inflammatory bowel disease and to the activation of these inflammatory cells. Lamina propria mononuclear cells isolated from colon tissue from 14 patients with inflammatory bowel disease (IBD) and from histologically normal controls were studied. Cells from IBD-affected tissue produced significantly more colony-stimulating factor activity (1402 +/- 252 U) per 2 x 10(6) cells than those from normal mucosa (362 +/- 85 U), mainly because of the increased production of granulocyte colony-stimulating factor and interleukin 1. This was accompanied by increases in the amount of specific messenger RNA for these two cytokines in lamina propria mononuclear cells from mucosa of patients with Crohn's disease (CD) compared with normal controls. By contrast, there was a substantial reduction in interleukin 3 production in CD and in ulcerative colitis lamina propria mononuclear cells, and this was reflected in significantly reduced expression of interleukin 3 messenger RNA in CD cells. Of the agents used in the therapy of IBD, hydrocortisone and 5-aminosalicylic acid, but not cyclosporin A, markedly suppressed in vitro production of cytokines by lamina propria mononuclear cells, suggesting that their therapeutic efficacy in vivo may be due in part to down-regulation of cytokine production in the inflamed mucosa.
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PMID:Enhanced mucosal cytokine production in inflammatory bowel disease. 137 Jun 62

We recently reported the presence of an organ-specific 40 kD colonic protein which acts as an autoantigen(s) in patients with ulcerative colitis. Using a specific monoclonal antibody directed against 40 kD protein (7E12H12, IgM isotype), in conjunction with immunocytochemistry and flow cytometry, we examined the presence of the 40 kD protein on human colon cancer cells, DLD-1, and also characterized the ability of cytokines, IFN-gamma and tumour necrosis factor, to modulate the expression of this protein on these tumour cells. The presence of the 40 kD protein was localized to the plasma membrane; less was present within the cytoplasm. Following exposure to IFN-gamma (10-1000 U/ml), DLD-1 colon tumour cells showed a dose- and time-dependent increase in 7E12H12 antibody associated immunofluorescence, with the maximum 7E12H12 antibody binding observed with 100 U/ml IFN-gamma at 48 h. In contrast, tumour necrosis factor did not alter the levels of anti-40 kD antibody binding over that of control cells. Since IFN-gamma is also known to induce class II major histocompatibility antigens, we examined the possibility of cross-reactivity of HLA class II antigens and Mr 40 kD epitope. Neither pre-incubation of DLD-1 colon tumour cells with anti-HLA class II antibodies followed by 7E12H12 nor co-incubation of both antibodies altered the amount of 7E12H12 antibody binding. Using a direct ELISA, a highly enriched preparation of Mr 40 kD protein reactive to anti-40 kD antibody did not react with HLA class II antibodies. The present results suggest that 40 kD protein is present on DLD-1 human colon tumour cells and that although the 40 kD protein epitope expression is increased by the lymphocyte-derived cytokine, IFN-gamma, the epitope is separate and distinct from the class II HLA antigens. Further studies on the 40 KD protein may elucidate its autoantigenic role in the pathogenesis of inflammatory bowel disease.
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PMID:Expression of the 40 kD protein in DLD-1 colon cancer cells and the effect of cytokines. 137 49

Interleukin-1 (IL-1) is a 17-kDa pro-inflammatory cytokine synthesized from a variety of cell types primarily in association with disease states or during host perturbation such as immune responses. At pM or even fM concentrations, IL-1 triggers various responses in nearly all cells. It appears that there is little or no major role for IL-1 in homoeostatic mechanisms. There are two IL-1's (alpha and beta) each with its distinct sequence; there are two IL-1 receptors. Disease states such as local and systemic infection, septic shock, degenerative arthritis and autoimmune diseases such as nephritis, vasculitis and inflammatory bowel disease appear to be mediated, in part, by IL-1. Organ failure, capillary leak and death occur in animals after a combination of tumour necrosis factor (TNF) and IL-1 which is more effective in inducing these changes than either cytokine alone. IL-1 is also a potent inducer of endothelial cell adhesion molecules, IL-6, and IL-8, a neutrophil chemotactic and activating factor. Strategies for reducing the effects of IL-1 have been based on suppression of transcription, translation, or secretion; more recently, receptor blockade has been a new approach. A naturally occurring IL-1-specific receptor antagonist (IL-1ra), which shares 40% conserved amino-acid homology with IL-1 beta, binds to IL-1 surface receptors with the same affinity as IL-1 but does not possess agonist activity and acts as a competitive inhibitor of IL-1. Studies using the IL-1ra to block endogenous IL-1 in a variety of animal disease models suggest that IL-1 plays a key role in triggering the cascade of inflammatory responses. In addition, the IL-1ra reduces the spontaneous production of growth factors and proliferation of leukaemic cells. The IL-1ra may be an advantageous therapy in patients with sepsis, diabetes, inflammatory bowel, arthritis and cancer.
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PMID:Reduction of inflammation by decreasing production of interleukin-1 or by specific receptor antagonism. 139 23

Fusidic acid is an antibiotic with T-cell specific immunosuppressive effects similar to those of cyclosporin. Because of the need for the development of new treatments for Crohn's disease, a pilot study was undertaken to estimate the pharmacodynamics and tolerability of fusidic acid treatment in chronic active, therapy-resistant patients. Eight Crohn's disease patients were included. Fusidic acid was administered orally in a dose of 500 mg t.d.s. and the treatment was planned to last 8 weeks. The disease activity was primarily measured by a modified individual grading score. Five of 8 patients (63%) improved during fusidic acid treatment: 3 at two weeks and 2 after four weeks. There were no serious clinical side effects, but dose reduction was required in two patients because of nausea. Biochemically, an increase in alkaline phosphatases was noted in 5 of 8 cases (63%), and the greatest increases were seen in those who had elevated levels prior to treatment. All reversed to pre-treatment levels after cessation of treatment. The results of this pilot study suggest that fusidic acid may be of benefit in selected chronic active Crohn's disease patients in whom conventional treatment is ineffective. Because there seems to exist a scientific rationale for the use of fusidic acid at the cytokine level in inflammatory bowel disease, we suggest that the role of this treatment should be further investigated.
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PMID:Treatment of Crohn's disease with fusidic acid: an antibiotic with immunosuppressive properties similar to cyclosporin. 142 Jul 41

Immunoregulatory properties of cytokines may mediate disordered inflammatory events in ulcerative colitis (UC) and Crohn's disease (CD). In the present study, profiles of cytokines produced by activated macrophages were studied in colonic tissue from 43 patients with and without inflammatory bowel disease (IBD). Cytokine messenger RNA (mRNA) extracted from mucosal biopsy specimens was studied using polymerase chain reaction assay techniques. A greater percentage of active UC samples had detectable levels of mRNA for interleukins (IL) 1, 6, and 8 and gro than samples in inactive UC and noninflammatory controls. These cytokines were comparable in active UC and inflammatory controls. Expression of gro mRNA in active UC tissue was significantly higher than in active CD. Tumor necrosis factor was detected in only 7 of 43 samples with no difference between groups. Active and inactive CD did not differ in percentage of cytokine mRNA expression. IL-1 receptor antagonist (IL-1ra) was detected in more inflammatory controls than in CD and was expressed in fewer IBD patients than IL-1. Expression of proinflammatory cytokines in grossly inactive CD and possible defective production of IL-1ra may explain disease reactivation and chronicity.
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PMID:Cytokine messenger RNA profiles in inflammatory bowel disease mucosa detected by polymerase chain reaction amplification. 142 79

The mucosal immune system consists of a number of compartments that are populated with a different assortment of cells and serve different functions. The cytokines produced by the cells in each of these compartments are currently being defined. This is best understood in relation to B cells, whose proliferation and maturation is guided by a sequence of cytokines. PP are inductive sites that preferentially stimulate IgA production. At least in part, this preference seems to be due to the T cells located in PP, which have been shown to stimulate switching to IgA production by cognate interactions and production of TGF-beta. Postswitch B cells expressing surface IgA respond to IL-5, a cytokine produced by T cells in GALT. Terminal differentiation to IgA-producing plasma cells in the lamina propria may be driven by IL-6, which can be produced by a variety of cells in the lamina propria and by epithelial cells. T cells in the lamina propria have an assortment of surface markers consistent with both activation and memory and appear to produce a variety of cytokines in the local environment that presumably act in normal host defense. IEL consist mainly of CD8+ T cells. They have been shown to produce IFN-gamma and, very likely, other cytokines that presumably act in a paracrine fashion on local enterocytes. How these cells and cytokines are perturbed during intestinal inflammation is currently being defined. A certain assortment of cytokines are greatly increased in IBD. This assortment, including IL-1, IL-6, and IL-8, is elevated in a wide variety of chronic inflammatory states in other tissues as well. A critical requirement for cytokines to exert their effects is the expression of specific receptors on target cells. Virtually nothing is known about this aspect of mucosal immunity, but receptor expression on mucosal cells must be defined before we will be able to understand the complex interactions among lymphoid cells, the cytokines they produce, and the local stromal and epithelial cells.
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PMID:Cells and cytokines in mucosal immunity and inflammation. 151 47

Continued delineation of the major factors that lead to intestinal inflammation will provide critical insights into many of the pathophysiologic events leading to tissue destruction in IBD. The exploration of exciting and important new areas, such as the role of adhesion molecules, proinflammatory cytokines, and the activation of lymphocytes and phagocytes, will contribute significantly to a better understanding of the mechanisms that sustain the intestinal inflammatory process. Determining the mechanisms of amplification and perpetuation of intestinal inflammation as well as learning more about the natural suppression of intestinal inflammation by the normal cellular and cytokine networks of the mucosal immune system will open exciting new therapeutic approaches. It is encouraging to see realistic and testable working models emerge from the combined efforts of many committed investigators who have been engaged in studying the role of the mucosal immune system in the pathophysiology of IBD. A great deal more remains to be learned in this rapidly advancing area, and we can look forward with confidence to continued advances in the study of IBD.
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PMID:The role of the mucosal immune system in inflammatory bowel disease. 151 51


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