UMLS:C0010346 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0010346 (Crohn's disease)
21,615 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Laminins are basement membrane molecules that mediate cell functions such as adhesion, proliferation, migration, and differentiation. In the normal small intestine, laminin-5 and -10 are mainly expressed at the base of villus cells. However, in Crohn's disease (CD), a major redistribution of these laminins to the crypt region of the inflamed ileal mucosa has been observed, suggesting a possible relationship between laminin expression and cytokine and/or growth factor production, which is also altered in CD. The aim of this study was to test the hypothesis that proinflammatory cytokines can modulate laminin expression by intestinal epithelial cells. The effect of TNF-alpha, IFN-gamma, IL-1beta, IL-6, and transforming growth factor (TGF)-beta was analyzed on the expression of laminins in the normal human intestinal epithelial crypt (HIEC) cell line. When treated with a single cytokine, HIEC cells secreted small amounts of laminin-5 and -10. Only TNF-alpha and TGF-beta induced a slight increase in the secretion of these laminins. However, in combination, TNF-alpha and IFN-gamma synergistically stimulated the secretion of both laminin-5 and -10 in HIEC cells. Transcript analyses suggested that the upregulation of the two laminins might depend on distinct mechanisms. Interestingly, the TNF-alpha and IFN-gamma combination was also found to significantly promote apoptosis. However, the effect of cytokines on the secretion of laminins was maintained even after completely blocking apoptosis by inhibiting caspase activities. These results demonstrate that laminin production is specifically modulated by the proinflammatory cytokines TNF-alpha and IFN-gamma in intestinal epithelial cells under an apoptosis-independent mechanism.
...
PMID:Proinflammatory cytokines TNF-alpha and IFN-gamma alter laminin expression under an apoptosis-independent mechanism in human intestinal epithelial cells. 1508 81

Type 1, or cellular, immune response is characterized by overproduction of IL-1, IL-2, IFN-gamma and TNF-alpha and is the underlying immune mechanism of some autoimmune disorders such as psoriasis, alopecia areata, rheumatoid arthritis, Crohn's disease, multiple sclerosis, insulin-dependent diabetes mellitus and experimental autoimmune uveitis. Type 2 immune response is seen in allergic and antibody-mediated autoimmune diseases and is characterized by IL-4, IL-6 and IL-10 overproduction. Linoleic acid is a precursor of prostaglandin E2 (PGE2) and its intake results in tissue production of PGE2, especially in the absence of other polyunsaturated fatty acids (PUFAS) which inhibit this conversion. PGE2 decreases the production of IL-1, IL-2, IFN-gamma and TNF-alpha and proliferation of TH1 cells and increases the production of IL-4, leading to suppression of the type 1 immune response. Taken together, linoleic acid, the major PUFA of maize oil, could have therapeutic efficacy against cellular autoimmune disorders. On the other hand, excessive intake of linoleic acid may aggravate type 2 autoimmune disorders.
...
PMID:The beneficial and detrimental effects of linoleic acid on autoimmune disorders. 1511 15

While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-gamma, whereas comparable cells from CD patients produce large amounts of IFN-gamma and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13-producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding alpha-galactosylceramide-loaded tetramers, and alpha-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161(+) LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.
...
PMID:Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. 1567 17

TNF can potentiate IFN-gamma production by activated T cells and other members of the TNF-superfamily play key roles in this effect. A newly discovered TNF-superfamily cytokine (TL1A) could also be involved in initiating or promoting the Th1 response by enhancing IFN-gamma production. The purpose of this study was to assess the role of recombinant TL1A on IFN-gamma production by cultured PBMC and lamina propria LPMC and to determine whether TL1A expression is altered in inflammatory bowel disease. IFN-gamma, but not IL-4 or IL-10 production by PBMC and LPL, was dose-dependently augmented by TL1A (or by activation of its receptor, death domain receptor 3 [DR3], with specific mAb) independently of, but in synergy with, IL-12 and IL-18. T cell activating stimuli induced expression of TL1A on the cell membrane (mb-TL1A) in a fraction of peripheral blood (PB) T cells. In the intestinal mucosa, a fraction of lamina propria (LP) T cells, especially CD4+ cells, constitutively expressed mb-TL1A, and the fraction increased in mucosal inflammation. A higher fraction of cells also express the TL1A receptor DR3 in ulcerative colitis and Crohn's disease. TL1A transcript was several times more abundant in RNA from mucosal biopsies taken from inflamed Crohn's disease lesions than in those taken from uninvolved areas. Expression of TL1A and its receptor DR3 by lamina propria mononuclear cells (LPMC) could have significant influence on the severity of mucosal inflammation.
...
PMID:Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. 1520 83

Immune system is a major determinant of pathophysiology of inflammatory bowel disease (IBD), and cytokines are well known mediators of immune system. Recently, informations on pro-inflammatory cytokines and their role in IBD have led to development of potential therapeutic approach to manipulate these cytokines and there by inhibiting inflammation in IBD. These therapeutic approaches include inhibitors of the tumour necrosis factor (TNF)-alpha lymphocyte trafficking, type 1 T helper (Th1) cell polarization and nuclear factor type beta; immunoregulatory cytokines and various growth factors. Studies on these therapies have documented variable results and the outcomes of many clinical trials are awaited. However, these potential therapies, if become real may revolutionise approach in patients with IBD. Analysis of the inflammed mucosa from patients with Crohn disease (CD) and ulcerative colitis (UC) have shown increased expression of certain proinflammatory cytokines such as interleukin-1 (IL-1), interleukin 6 (IL-6) and TNF-alpha. The latter is important in the recruitment of neutrophils into inflammed tissue, a process which results from three physiological steps: (i) rolling, (ii) adhesion, and (iii) transendothelial migration. Understanding of the biology of chronic inflammation has expanded the therapies available for IBD and particularly CD. At present, the biological therapies that are being used in clinical practice or investigated for the treatment of IBD are predominantly proteins, usually delivered intravenously or subcutaneously. The therapies used include: 1. TNF-alpha inhibitors: infliximab, CDP 571, etanercept, onercept, CNI- 1493 and thalidomide. 2. Inhibitors of lymphocyte trafficking: natalizumab, LPD-02 and ICAM-1. 3. Inhibitors of Th1 polarization: monoclonal antibodies for IL-12, interferon (IFN)-gamma and anti IFN-gamma. 4. Immunoregulatory cytokines: IL-10 and IL-11. 5. Inhibitors of nuclear factor kappa (beta NF-kbeta.) 6. Growth factors: epidermal growth factor (EGF) and Keratinocyte growth factor (KGF).
...
PMID:Recent advances in biological therapy for inflammatory bowel disease. 1530 63

Crohn's disease and ulcerative colitis are examples of inflammatory bowel disease (IBD), and are multifaceted chronic autoimmune disorders with unknown etiology; to date, there is no known cure. IBD is thought to occur as a result of an inappropriate immune response to environmental factors in a genetically predisposed host, and it has become increasingly clear that cytokines play an important role in this process. In recent years, several groups have provided evidence that IL-18 is significantly up-regulated during the course of chronic intestinal inflammation and appears to play a pivotal role in the pathogenesis of human IBD, particularly in Crohn's disease. IL-18 is a pleiotropic cytokine with several biological functions, but is most commonly associated with its ability to synergistically induce the expression of IFN-gamma. However, although IL-18 has been extensively studied in both human IBD as well as in murine models of colitis, no definitive function of IL-18 during the initiation and perpetuation of chronic gut inflammation has been firmly established, and its precise role in the pathogenesis of IBD has yet to be determined. In light of the recent observation that the transcription factor interferon regulatory factor-1 has the ability to regulate the functional activity of IL-18, and concomitantly disease severity, in a murine model of colitis through altered expression of its endogenous inhibitor, IL-18-binding protein, this commentary will review what is currently known regarding the role of IL-18 in normal mucosal immunity and during the pathogenesis of IBD.
...
PMID:Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe? 1530 67

1 A novel animal model of spontaneous colonic inflammation, the multiple drug-resistant (mdr1) a(-/-) mouse, was identified by Panwala and colleagues in 1998. The aim of our study was to further characterise this model, specifically by measuring cytokines that have been implicated in inflammatory bowel disease (IBD) (IL-8 and IFN-gamma) in the colon/rectum of mdr1a(-/-) mice, and by determining the sensitivity of these, together with the macroscopic, microscopic and disease signs of colitis, to dexamethasone (0.05, 0.3 and 2 mg kg(-1) subcutaneously (s.c.) daily for 7 days). 2 All mdr1a(-/-) mice had microscopic evidence of inflammation in the caecum and colon/rectum, while control mice with the same genetic background did not. Significant increases in colon/rectum and caecal weights and also in cytokine levels (both IFN-gamma and IL-8) in homogenised colon/rectum were observed in mdr1a(-/-) mice compared to mdr1a(+/+) mice. 3 Dexamethasone reduced the increases in tissue weights and also microscopic grading of colitis severity, but had no effect on IFN-gamma or IL-8. 4 This study supports the similarity of the gastrointestinal inflammation present in mdr1a(-/-) mice to that of human IBD, in particular Crohn's disease. This has been demonstrated at the macroscopic and microscopic levels, and was supported further by elevations in colonic levels of IFN-gamma and IL-8 and the disease signs observed. The incidence of colitis was much higher than previously reported, with all mice having microscopic evidence of colitis. The limited variance between animals in the parameters measured suggests that this model is reproducible.
...
PMID:Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene. 1546 45

CD4(+) T helper cells are important for the regulation of immune responses in the intestinal mucosa and they exert their effects through the secretion of pro-inflammatory and immunomodulatory cytokines. Human patients with inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis have alterations in the normal intestinal cytokine profile. These cytokine abnormalities have been shown at both the protein and messenger RNA (mRNA) level. The role that mucosal cytokines play in the pathogenesis of canine IBD has only been investigated using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis of gut tissue, as cytokine antisera are not available for this species. Real-time RT-PCR has been recognised to be a more accurate and sensitive method of quantifying mRNA transcripts, so in this study TaqMan real-time RT-PCR assays for the quantification of mRNA encoding IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-18, IFN-gamma, TNF-alpha and TGF-beta in canine intestinal mucosa were developed. The amount of these templates was quantified in normal canine duodenal mucosa (n = 8). IL-18, TGF-beta and TNF-alpha were found to be the most abundant transcripts, with IL-10 and IFN-gamma present at levels approximately 10-fold less. IL-2, IL-4, IL-5, IL-6 and IL-12 were the least abundant templates, with some RNA samples having no detectable mRNA copies. The methods developed in this study will form the basis of further work investigating the expression of mRNA encoding cytokines in mucosa from dogs with chronic enteropathies. In addition, these real-time PCR assays can also be used for the quantification of canine cytokine mRNA in other diseases.
...
PMID:Cytokine mRNA quantification in histologically normal canine duodenal mucosa by real-time RT-PCR. 1562 66

Chemokine receptors play an important role in the recruitment of activated T cells to inflammatory sites. The aim of this study was to analyze the expression of the chemokine receptor CXCR3 on T lymphocytes in intestinal lymphoid tissues and to document the altered disposition of these cells in patients with inflammatory bowel disease (IBD). The expression and regulation of CXCR3 on mucosal lymphoid tissue and peripheral blood lymphocytes (PBLs) were analyzed by flow cytometry and Northern blotting. The migration of lamina propria lymphocytes (LPLs) and PBLs to interferon (IFN)-gamma-inducible protein (IP)-10 (or CXCL10) was evaluated by chemotaxis assays. IFN-gamma and interleukin-4-producing T lymphocytes were quantitated by intracellular staining, and IFN-gamma was measured in culture supernatants by enzyme-linked immunosorbent assay. CXCR3 is expressed on the majority of CD4 lamina propria (LP) T cells and correlates with a T-helper (Th) type 1/Th-0 cytokine phenotype on LP and mesenteric lymph node (MLN) CD4 T lymphocytes. IP-10/CXCL10 is more chemotactic in vitro for both CD4 and CD8 T cells that have been isolated from the LP compared with peripheral blood. CXCR3 protein, but not messenger RNA, expression was lower in inflamed LPLs compared with uninvolved LPLs in patients with ulcerative colitis but not in those with Crohn's disease. However, CXCR3 was expressed on a higher percentage of MLN CD4 T cells isolated from inflamed intestinal tissue, and CXCR3 expression could be induced in vitro with T-cell activation in MLN CD4 T cells. In summary, most CXCR3 T lymphocytes in normal intestinal tissues are Th-1/Th-0 effector/memory cells. Activation-dependent receptor regulation and alteration in receptor-bearing cells, primarily in MLN draining inflamed intestinal tissue, suggest an important role for this T-cell subset in the pathogenesis of human IBD.
...
PMID:Expression and regulation of the chemokine receptor CXCR3 on lymphocytes from normal and inflammatory bowel disease mucosa. 1562 97

CD4+ T cells are essential for development and perpetuation of Crohn's disease, a chronic immune-mediated condition that affects primarily the small intestine. Using novel models of Crohn's disease-like ileitis (i.e., SAMP1/YitFc and CD4+ T cell transfer models), we have begun to understand the adhesive pathways that mediate lymphocyte trafficking to the chronically inflamed small bowel. Expansion of the CD4/beta7+ population and increased mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression were observed within the intestinal lamina propria with disease progression. However, Ab blockade of the beta7 integrin, the alpha4beta7 heterodimer, MAdCAM-1, or L-selectin did not attenuate inflammation. Blockade of two pathways (L-selectin and MAdCAM-1 or alpha4 integrins) was required to improve ileitis. Further analyses showed that 55 +/- 7% of the mesenteric lymph node alpha4beta7+CD4 expressed L-selectin. These L-selectin+ T cells were the main producers of TNF-alpha and the predominant ileitis-inducing subpopulation. Mechanistically, combined blockade of L-selectin and MAdCAM-1 depleted the intestinal lamina propria of CD4+ T cells that aberrantly coexpressed alpha4beta7 and alpha4beta1 integrins, markedly decreasing local production of TNF-alpha and IFN-gamma. Thus, pathogenic CD4+ T cells not only use the physiologic alpha4beta7/MAdCAM-1 pathway, but alternatively engage alpha4beta1 and L-selectin to recirculate to the chronically inflamed small intestine.
...
PMID:L-selectin, alpha 4 beta 1, and alpha 4 beta 7 integrins participate in CD4+ T cell recruitment to chronically inflamed small intestine. 1569 71

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>