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)

Eosinophils may be prominent in intestinal diseases including allergic gastroenteritis, inflammatory bowel disease, enteritis associated with hypereosinophilic syndromes (HES), and parasitic diseases. Unlike normal blood eosinophils, those that circulate in HES and those that infiltrate inflamed tissue exhibit an "activated" phenotype. To model intestinal epithelial-eosinophil interactions, we used peripheral blood eosinophils and human crypt-like T84 epithelial cell-line monolayers. Eosinophils from normal, mildly atopic donors, only if activated by PMA or primed with granulocyte-macrophage-CSF for 48 h, as well as eosinophils from HES patients elicited a short circuit current when applied apically to T84 monolayers. This eosinophil-derived bioactivity, which was transferable in cell-free supernatants and in < 1000 m.w. ultrafiltrates, stimulated electrogenic Cl- secretion, as indicated by inhibition with basolateral bumetanide or gluconate substitution and by enhancement of the rate constant for 125I efflux from preloaded T84 cells. This secretagogue activity was blocked in both intact activated eosinophils and in eosinophil-conditioned supernatants, by 8-phenyl-theophylline, indicating involvement of an adenosine receptor. Ion exchange and reversed-phase HPLC analyses demonstrated that eosinophil supernatant ultrafiltrates contained elevated levels of 5'-AMP that was converted to adenosine after incubation with epithelium. Inhibition of epithelial apical membrane ecto-5'-nucleotidase ablated the conversion to adenosine. These studies establish that activated eosinophils elicit Cl- secretion from intestinal epithelial and that 5'-AMP released by eosinophils followed by its conversion to adenosine at the epithelial surface is the basis for this response.
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PMID:Activated eosinophils evoke chloride secretion in model intestinal epithelia primarily via regulated release of 5'-AMP. 822 57

Ulcerative colitis (UC) and Crohn's disease (CD) are immunologically mediated disorders characterized by a chronic, relapsing inflammatory response. Elevation of several cytokines, with important immunoregulatory and proinflammatory activities have been demonstrated during active inflammatory bowel disease (IBD). These cytokines, including interleukin-1 (IL-1), IL-6, IL-8 and GM-CSF, may play an important role in the initiation and amplification of the inflammatory response leading to intestinal injury. There is increasing evidence that IL-1 is activated early in the cascade of events leading to inflammation. Therefore, IL-1 has been implicated as a primary target for therapeutic intervention for the treatment of several inflammatory diseases, including IBD. In addition, a mucosal imbalance of intestinal IL-1 and IL-1ra is present in patients with IBD, suggesting that insufficient production of endogenous IL-1ra may contribute to the pathogenesis of chronic gut inflammation. Preliminary studies examining the association between newly described polymorphisms in the IL-1 gene cluster and IBD have provided new insight into the genetic predisposition to UC. This article will review current progress in understanding the role of Il-1 and Il-1ra in IBD, as well as discuss recently described polymorphisms in the Il-1 gene cluster and their association with UC and CD.
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PMID:Interleukin-1 and interleukin-1 receptor antagonist in inflammatory bowel disease. 889 1

Glucocorticoids inhibit the expression and action of most cytokines. This is part of the in vivo feed-back system between inflammation-derived cytokines and CNS-adrenal produced corticosteroids with the probable physiological relevance to balance parts of the host defence and anti-inflammatory systems of the body. Glucocorticoids modulate cytokine expression by a combination of genomic mechanisms. The activated glucocorticoid-receptor complex can (i) bind to and inactivate key proinflammatory transcription factors (e.g. AP-1, NF kappa B). This takes place at the promotor responsive elements of these factors, but has also been reported without the presence of DNA; (ii) via glucocorticoid responsive elements (GRE), upregulate the expression of cytokine inhibitory proteins, e.g. I kappa B, which inactivates the transcription factor NF kappa B and thereby the secondary expression of a series of cytokines; (iii) reduce the half-life time and utility of cytokine mRNAs. In studies with triggered human blood mononuclear cells in culture, glucocorticoids strongly diminish the production of the 'initial phase' cytokines IL-1 beta and TNF-alpha and the 'immunomodulatory' cytokines IL-2, IL-3, IL-4, IL-5, IL-10, IL-12 and IFN-gamma, as well as of IL-6, IL-8 and the growth factor GM-CSF. While steroid treatment broadly attenuates cytokine production, it cannot modulate it selectively, e.g. just the TH0, the TH1 or the TH2 pathways. The production of the 'anti-inflammatory' IL-10 is also inhibited. The exceptions of steroid down-regulatory activity on cytokine expression seem to affect 'repair phase' cytokines like TGF-beta and PDGF. These are even reported to be upregulated, which may explain the rather weak steroid dampening action on healing and fibrotic processes. Some growth factors, e.g. G-CSF and M-CSF, are only weakly affected. In addition to diminishing the production of a cytokine, steroids can also often inhibit its subsequent actions. Because cytokines work in cascades, this means that steroid treatment can block expression of the subsequent cytokines. The blocked cytokine activity does not depend on a reduced cytokine receptor expression; in fact available in vitro investigations show that while the cytokine expression is blunted, its receptor is upregulated. The cellular studies presented here may represent the maximum potential of steroids to modulate cytokine expression in human mononuclear cells. It remains to be determined by clinical-experimental studies how effective cytokine modulation can be achieved in situ in inflamed bowel by systemic or by topical steroid therapy. Such studies may also answer whether a blocked cytokine production/action is the key or just a secondary mechanism behind the unique efficacy of steroids in active inflammatory bowel disease.
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PMID:Cytokine modulation by glucocorticoids: mechanisms and actions in cellular studies. 889 6

Inflammatory bowel disease is associated with mucosal neutrophil recruitment and activatation, mediated in part by arachidonic acid metabolites. G-CSF attenuates the immune response to sepsis and ameliorates glycogen storage disease Ib-related colitis. These actions may be effected through the shedding of neutrophil adhesion molecules, or inhibition of proinflammatory mediator synthesis. Immune complex colitis was used to evaluate the effect of rhG-CSF on colonic mucosal inflammation, neutrophil recruitment and the generation of eicosanoids. Immune complex colitis was induced in White New Zealand rabbits. Animals were pretreated with rhG-CSF either 24 h before induction, or at induction, with dosages of 50 and 200 micrograms/kg. rhG-CSF caused a time- and dose-dependent neutrophilia in all animals. Pretreatment with rhG-CSF resulted in increased tissue myeloperoxidase levels, despite a histologically similar mucosal polymorphonuclear cell infiltrate between treated and control colitis groups. Leukotriene B4 (LTB4) and thromboxane B2 (TXB2) dialysis fluid levels were lower in treated animals, in particular in the groups receiving two doses (LTB4: both P < 0.01; TXB2: both P < 0.01. Prostaglandin E2 (PGE2) levels in dialysis fluid of the rhG-CSF-treated animals showed no difference from controls. In this model of experimental colitis, high-dose therapy with G-CSF resulted in a marked decrease of proinflammatory mediators, but mucosal generation of the protective PGE2 was preserved. These results suggest that prolonged high-dose therapy with G-CSF may have anti-inflammatory effects in colitis.
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PMID:Efficacy of recombinant granulocyte colony-stimulating factor (rhG-CSF) in experimental colitis. 897 23

Products of an activated immune system may affect cells within the immune system as well as nonlymphoid cells in the local environment. Given the immunologically activated state of the intestinal tract, it is conceivable that locally produced cytokines could regulate epithelial cell function. To assess whether epithelial cells are targets for particular cytokines, we initiated studies on the binding of a panel of proinflammatory cytokines in freshly isolated epithelial cells from normal and inflammatory bowel disease (IBD) patients as well as in cell lines. Isolated intestinal epithelial cells (IEC) were stained with phycoerythrin-conjugated or biotinylated cytokines to determine the expression and density of receptors for IL-1beta, IL-6, granulocyte-macrophage CSF (GM-CSF), and TNF-alpha. Receptors for IL-1beta, IL-6, and GM-CSF were readily detectable in all epithelial cell preparations at levels equal to (GM-CSFR) or lower than those seen on monocytes. However TNFalpha-R were not detectable on freshly isolated IECs. Receptor density was greater in surface vs crypt epithelial cells, but no significant differences were seen between normal and IBD epithelial cells. Expression of IL-1R and IL-6R was enhanced by LPS and IFN-gamma. Functionally, IL-1beta enhanced proliferation of the IEC cell line, DLD1, whereas GM-CSF treatment of de-differentiated crypt-like DLD1 and HT29 cells resulted in enhanced expression of ICAM-1. Furthermore, TNF-alpha treatment enhanced the secretion of IL-8 and GRO-alpha in HT29 cells, but not in freshly isolated IEC cultures. The differential binding and function of proinflammatory cytokines on IEC support the hypothesis that these cytokines may be involved in normal physiological processes as well as in regulating mucosal immune responses.
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PMID:The regulation and functional consequence of proinflammatory cytokine binding on human intestinal epithelial cells. 975 92

Chronic inflammatory bowel disease (IBD)-like colitis is occasionally associated with glycogen storage disease-type 1b (GSD-1b). We describe a 17-year old boy with GSD-1b who developed an IBD-like colitis. Roentgenography and colonoscopy showed the lead-pipe appearance of the colon and circumferential ulcers. Histopathologic examination revealed nonspecific inflammation without granulomatous lesions. High-dose granulocyte-colony stimulating factor (G-CSF) and sulfasalazine led to the resolution of the colitis, although neutropenia continued. Besides this case, 10 published cases of GSD-1b and IBD-like colitis were reviewed. All cases had severe neutropenia and/or neutrophil dysfunction. The mean onset of bowel disease was 12.3 years of age. Seven cases required surgical treatment. All five patients with G-CSF/GM-CSF therapy showed clinical remission. These findings suggest that IBD-like colitis is a grave complication of GSD-1b and that recurrent enteric infections due to neutrophil deficiency may contribute to the development of this bowel disease.
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PMID:Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. 1138 85

Mucosal macrophages have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Macrophage-colony stimulating factor (M-CSF) influences monocyte/macrophage proliferation, differentiation, and activation. Serum levels are increased in active IBD, but little is known about its role in mucosal inflammation. This study was undertaken to determine the distribution, frequency, and level of M-CSF expression in normal and IBD-affected intestine. RNA and tissue were studied from patients with Crohn's disease (CD) and ulcerative colitis (UC) as well as from histologically normal colon. Tissue from intestinal tuberculosis and ischaemic colitis patients served as controls. M-CSF mRNA and protein were examined by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridisation, and immunohistochemistry, respectively. M-CSF mRNA and protein were detected in histologically normal intestine, but their expression was largely confined to the mucosa. In active IBD, the frequency of M-CSF-expressing cells was significantly increased and their distribution markedly altered, although no increase in mucosal M-CSF mRNA levels in intestinal tissue was observed. The changes were not specific to IBD, as there were similar findings in intestinal tuberculosis and ischaemic colitis. The marked alteration observed in M-CSF expression in IBD and the importance of this cytokine in stimulating macrophage functions suggest that M-CSF may contribute to the pathogenesis of the IBD lesion.
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PMID:Expression of macrophage-colony stimulating factor in normal and inflammatory bowel disease intestine. 1174 98

Therapeutic options for patients with refractory ulcerative colitis or Crohn's disease have recently been augmented by the introduction of biological therapies. The pro-inflammatory cytokine, tumor necrosis factor (TNF)-alpha is present in elevated concentrations in patients with inflammatory bowel disease and inhibitors of TNF alpha have proved effective as treatment. Strategies aimed at reducing TNF in patients with Crohn's disease, include the mouse/human chimeric monoclonal antibody, infliximab (Centocor Inc), the humanized monoclonal antibody, CDP-571 (Celltech Group plc), the human recombinant TNF receptor fusion protein, etanercept (Immunex Corp), and thalidomide. New approaches, including the use of soluble TNF receptors, appear promising. This article reviews the evidence of therapeutic inhibition of TNF.
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PMID:Therapeutic inhibitors of tumor necrosis factor in Crohn's disease. 1249 4

Substance P (SP) is a neuropeptide which is widely distributed in the periphery and the central nervous system (CNS), where it is co-localised with other neurotransmitters such as serotonin or dopamine and where it acts as a neuromodulator. SP has been proposed to play a role in the aetiopathology of asthma, inflammatory bowel disease, emesis, psoriasis, as well as neuropsychiatric disorders including pain syndromes (e.g. migraine and fibromyalgia) and affective disorders, anxiety disorders, schizophrenia and Alzheimer's disease. This review focuses on the role of SP in the pathogenesis of affective disorders. It summarises the current knowledge on measurements of SP in the CSF and serum in patients with depressive disorders or fibromyalgia, effects of SP-application in humans, SP-receptor expression in postmortem brains and the modulation of SP levels in the course of antidepressant treatment. It also discusses the promise of substance P-receptor antagonists (SPA) for the treatment of affective disorders and their proposed mechanism of action. In summary, much more research is needed to elucidate the role of SP in the pathogenesis of depression. SPA are promising as future drugs for the treatment of affective disorders, but current clinical trials have yet to be completed to draw a firm conclusion. Key words: substance P, neurokinin1-receptor, affective disorders, depression, review.
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PMID:Substance P and Substance P receptor antagonists in the pathogenesis and treatment of affective disorders. 1269 75

Our understanding of the etiology and pathogenesis of IBD has improved extensively over the past years. At the center of the pathogenesis seems to be an excessive pro-inflammatory immune reaction towards normal intestinal flora. The different factors involved in this concept will form the focus of this review. The initial phase of antigen processing and presentation can be influenced by either modulation of the intestinal flora via antibiotics or probiotics or by direct stimulation of macrophages through GM-CSF treatment. Antigen recognition and activation of T-cells can be down-regulated by immunosuppressives such as azathioprine, CsA or methotrexate thus building the basis for current treatment in IBD. The pro-inflammatory character of the immune reaction is defined by the predominance of certain T-cell subpopulations. By targeting cytokines the disbalance of these subpopulation should be reconstituted. Here we will focus first on preliminary clinical as well as experimental data for the pro-inflammatory mediators IL-12 and IL-18 as well as for the anti-inflammatory cytokine IL-10. Second, the clinical data for the TNFalpha antibody that has been proven to be efficacious in Crohn's disease and the associated risks will be discussed. Last, recent clinical and experimental data on targeting cell adhesion as well as intracellular signaling pathways will be presented. In summary, with regard to this review, treatments, which intervene as early as possible in the initiation of the pathological immune reaction and simultaneously have a favorable side-effect profile, must be the focus of future research.
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PMID:Therapeutic approaches in inflammatory bowel disease based on the immunopathogenesis. 1563 10


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