Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Following the present concepts, the synthetic sphingosine analog of myriocin FTY720 alters migration and homing of lymphocytes via sphingosine 1-phosphate receptors. However, several studies indicate that the immunosuppressive properties of FTY720 may alternatively be due to tolerogenic activities via modulation of dendritic cell differentiation or based on direct effects on CD4(+)CD25(+) regulatory T cells (Treg). As Treg play an important role for the cure of inflammatory colitis, we used the Th1-mediated 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model to address the therapeutic potential of FTY720 in vivo. A rectal enema of TNBS was given to BALB/c mice. FTY720 was administered i.p. from days 0 to 3 or 3 to 5. FTY720 substantially reduced all clinical, histopathologic, macroscopic, and microscopic parameters of colitis analyzed. The therapeutic effects of FTY720 were associated with a down-regulation of IL-12p70 and subsequent Th1 cytokines. Importantly, FTY720 treatment resulted in a prominent up-regulation of FoxP3, IL-10, TGFbeta, and CTLA4. Supporting the hypothesis that FTY720 directly affects functional activity of CD4(+)CD25(+) Treg, we measured a significant increase of CD25 and FoxP3 expression in isolated lamina propria CD4(+) T cells of FTY720-treated mice. The impact of FTY720 on Treg induction was further confirmed by concomitant in vivo blockade of CTLA4 or IL-10R which significantly abrogated its therapeutic activity. In conclusion, our data provide clear evidence that in addition to its well-established effects on migration FTY720 leads to a specific down-regulation of proinflammatory signals while simultaneously inducing functional activity of CD4(+)CD25(+) Treg. Thus, FTY720 may offer a promising new therapeutic strategy for the treatment of IBD.
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PMID:FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells. 1727 53

In their review, the authors state that the very low incidence and prevalence of IBD in sub-Saharan Africa cannot be explained by genetic factors since in Black populations of the U.S.A. and U.K., the incidence of these diseases is approaching that of the white populations. Beside helminths whose intestinal infestation is frequent in sub-Saharan Africa, other micro-organisms such as atypical mycobacteria, lactobacilli, etc, might have been reduced in Western population. This is a new variant of the Hygiene hypothesis. After Rook et al., these micro-organisms were acting as adjuvants for induction of T regulatory cells which, associated with antigen-presenting cells secrete IL-10 and TGF-beta, inhibiting the maturation of CD4 T cells to Th1 and Th2 effector cells, and consequently reducing the occurrence of Th1-mediated diseases like Crohn's disease and Th2-mediated diseases like ulcerative colitis. The effects of intestinal helminths on host immunity have been studied in Ethiopian Jews emigrated to Israel. Thorough studies before and after deworming have demonstrated that chronic helminth infestation provokes a state of chronic immune activation with anergy, reversible after deworming. Administration of ova of Trichuris suis, an helminth non pathogenic in man, has given encouraging results in the treatment o Crohn's disease and ulcerative colitis with a good safety record but long-term trials are needed since the potentially harmful effects of helminths on immunity.
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PMID:Intestinal helminths: a clue explaining the low incidence of inflammatory bowel diseases in Subsaharan Africa? Potential benefits and hazards of helminth therapy. 1963 90

IBD is characterized by uncontrolled immune responses in inflamed mucosa, with dominance of IL-17-producing cells and deficiency of Treg cells. The aim of this study was to explore the effect and mechanisms of RA, the ligand of RARalpha, on immune responses in human and murine colitis. Colonic biopsies from patients with UC were cultured and treated with RA as the agonist of RARalpha or LE135 as the antagonist of RARalpha. Expressions of IL-17 and FOXP3 were detected by immunohistochemistry. Murine colitis was induced by intrarectal administration with TNBS at Day 1. Mice were then i.p.-treated with RA or LE135 daily for 7 days. Cytokine levels in the cultures of mouse LPMCs were measured. Expressions of FOXP3 and IL-17 in colon tissues or MLN were detected by immunohistological analysis. Body weight and colon inflammation were evaluated. RA treatment up-regulated FOXP3 expression and down-regulated IL-17 expression in colon biopsies of patients and in colon tissues and MLN of mice with colitis compared with controls. LPMCs from RA-treated mice produced lower levels of proinflammatory cytokines (TNF-alpha, IL-1beta, IL-17) but more regulatory cytokines (IL-10, TGF-beta) compared with that of untreated mice. LE135 showed the opposite effect of RA. Furthermore, RA ameliorated TNBS-induced colitis in a dose-dependent manner, as seen by improved body weight and colon inflammation. RA down-regulates colon inflammatory responses in patients with IBD in vitro and in murine colitis in vivo, representing a potential therapeutic approach in IBD treatment.
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PMID:All-trans retinoic acid down-regulates inflammatory responses by shifting the Treg/Th17 profile in human ulcerative and murine colitis. 1947 11

Hyperactivation and hyperpermeability of the intestinal epithelium is a hallmark of IBD. AM has been shown to reduce the severity of colitis in the acetic acid and TNBS-induced colitis model, however the mechanism of the therapeutic effect of AM against the colitis has not been clarified. Here, we show that the protective capability of AM is associated with suppression of inflammation and maintenance of the intestinal epithelial barrier function. In the DSS-induced colitis model, intra-rectal AM-treated mice showed a reduction in loss of body weight and severity of colitis. AM-treatment suppressed phosphorylation of STAT1 and STAT3 in the colonic epithelium, and altered the cytokine balance in the intestinal T cells, with lower levels of IFN-gamma and TNF-alpha but higher levels of TGF-beta. Expression of the epithelial intercellular junctions such as tight and adherence junctions were sustained in the AM-treated mice. In contrast, the epithelial junctions were down-regulated in the control mice, leading to loss of epithelial barrier integrity and enhanced permeability. Collectively, these data indicate a broad spectrum of AM-induced effects with respect to protection against DSS-induced colitis, and suggest a potential therapeutic value of this treatment for IBD.
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PMID:Adrenomedullin treatment reduces intestinal inflammation and maintains epithelial barrier function in mice administered dextran sulphate sodium. 1978 Sep 71

Canine inflammatory bowel disease is a group of chronic enteropathies characterized by persistent or recurring gastric symptoms with an unknown etiology which are related to histopathological changes in the mucosa of the small and large bowel in the form of cellular infiltration in the mucosal lamina propria. Recent years have witnessed a growing number of investigations into the role of the immune system and, in particular, cytokines in the development of IBD. In this article, the expression of pro-inflammatory (IL-1, IL-2, IL-5, IL-6, IL-12, IL-18, IFN-gamma, TNF-alpha) and anti-inflammatory cytokines (IL-4, IL-10) was compared in canine patients with IBD based on clinical presentation, breed, lamina propria cell infiltrate and histopathological grade. Only selected studies confirmed higher mRNA expression levels of cytokines IL-2, IL-4, IL-5, IL-12p40, IFN-gamma, TNF-alpha and TGF-beta in dogs with IBD in comparison with healthy subjects. GSD were strongly represented in most study populations. Dogs with LPE were characterized by elevated levels of IL-1alpha, IL-1beta, IL-2, IL-5, IL-6, IL-12, TNF-alpha, TGF-beta. The present studies of canine patients with LPC revealed the mRNA expression of cytokines IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p35, IL-12p40, IFN-gamma, TNF-alpha, TGF-beta. In the reviewed studies, the progression of IBD was not accompanied by changes in the mRNA express-
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PMID:Cytokines in canine inflammatory bowel disease. 2369 93

Much of our understanding of gut-microbial interactions has come from mouse models. Intestinal immunity is complex and a combination of host genetics and environmental factors play a significant role in regulating intestinal immunity. Due to this complexity, no mouse model to date gives a complete and accurate representation of human intestinal diseases, such as inflammatory bowel diseases. However, intestinal tissue from patients undergoing bowel resection reflects a condition of severe disease that has failed treatment; hence a more dynamic perspective of varying inflammatory states in IBD could be obtained through the analyses of pinch biopsy material. Here we describe our protocol for analyzing mucosal pinch biopsies collected predominantly during colonoscopies. We have optimized flow cytometry panels to analyze up to 8 cytokines produced by CD4+ and CD8+ cells, as well as for characterizing nuclear proteins and transcription factors such as Ki67 and Foxp3. Furthermore, we have optimized approaches to analyze the production of cytokines, including TGF-beta from direct ex vivo cultures of pinch biopsies and LPMCs isolated from biopsies. These approaches are part of our workflow to try and understand the role of the gut microbiota in complex and dynamic human intestinal diseases.
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PMID:Isolation and cytokine analysis of lamina propria lymphocytes from mucosal biopsies of the human colon. 2576 17