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

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

To define mediator profiles in inflamed and noninflamed areas in inflammatory bowel disease (IBD) we analyzed the expression of 35 messenger-RNAs (mRNAs) encoding cytokines, chemokines, and some related molecules in transmural gut tissues (n=138) from patients with ulcerative colitis (UC), Crohn's disease (CD), and inflammatory and normal controls by real-time quantitative reverse transcription polymerase chain reaction. Using sample collectives with a comparable degree of inflammation, most parameters investigated showed similarly increased mRNA expression levels in both active UC and CD. This included proinflammatory cytokines, but also interferon (IFN) gamma and several IFN-gamma inducible chemokines. Only macrophage inflammatory protein (MIP)-2alpha mRNA was expressed at higher levels in inflamed UC vs. CD. IH revealed that MIP-2alpha protein was produced mainly by intestinal epithelial cells. Importantly, in histologically noninflamed/inactive IBD samples mRNAs for several mediators were significantly enhanced, accompanied by elevated levels of migration-inhibition factor related protein (MRP) 14 transcripts. CD14 positive macrophages were found especially in noninflamed/inactive UC, many of which coexpressed the RFD-7 antigen. Our results indicate a substantial overlap in cytokine/chemokine mRNA expression in UC and CD. Elevated mediator expression is evident in noninflamed/inactive areas in both diseases. Local recruitment of MRP-14 positive leukocytes might contribute to this phenomenon. In inactive UC a phenotypically altered population of macrophages expressing CD14 might play an additional role.
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PMID:Cytokine/chemokine messenger-RNA expression profiles in ulcerative colitis and Crohn's disease. 1244 82

Mucosal changes in inflammatory bowel disease (IBD) are characterized by ulcerative lesions accompanied by prominent cellular infiltrates in the bowel wall. Chemokines are chemotactic cytokines that are able to promote leukocyte migration to areas of inflammation and are also able to initiate cell activation events. They have recently been implicated in the pathophysiology of many disease states. The aim of this study was to detail the degree and distribution of specific chemokines, interleukin (IL)-8, monocyte chemoattractant protein (MCP)-1, -2, and -3, and macrophage inflammatory protein (MIP)-1alpha and -1beta, in IBD mucosa. Thirty-nine patients were included, ten controls, 20 ulcerative colitis (UC), and nine Crohn's disease (CD), with a range of disease activity. Colonic mucosal biopsies were collected from UC, CD, and control patients and embedded in glycol methacrylate. Two-micrometre-thick sections were cut and stained using immunohistochemistry for chemokine protein expression. Sections were analysed using a light microscope. Expression of all types of chemokine protein was detected in colonic mucosa from both control and IBD patients. Patterns of staining between IBD patients and controls differed significantly, but CD and UC patients demonstrated similar patterns of staining. Individual chemokine expression was found to be significantly up-regulated in IBD when patients were compared with the non-diseased group in all areas of the mucosal sections. Up-regulated chemokine expression correlated with increasing activity of the disease. It is concluded that human colonic chemokine expression is non-selectively up-regulated in IBD. The results supported the hypothesis that the degree of local inflammation and tissue damage in UC and CD is dependent on local expression of specific chemokines within IBD tissues.
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PMID:Chemokine expression in IBD. Mucosal chemokine expression is unselectively increased in both ulcerative colitis and Crohn's disease. 1247 23

Several chemokine receptors are expressed selectively on the surface of T cells depending on their polarization. The aim of this study was to characterize chemokine receptor expression in peripheral blood memory T cells in Crohn's disease (CD) and ulcerative colitis (UC), and to correlate the expression with disease activity. Peripheral blood mononuclear cells (PBMCs) were obtained from 24 patients with CD, 30 patients with UC, 24 normal controls and 10 disease controls. PBMCs were stained by anti-CCR3, CCR4, CCR5, CXCR3, CD4, CD8, CD45RO and beta 7 integrin, and the expression of the chemokine receptors were determined by flow cytometry. CCR4 expression on memory T cells was significantly lower in UC than in CD or normal controls, and that of memory CD4+ T and beta 7(high) memory CD4+ T cells was significantly higher in CD than in UC or normal controls. CCR4 expression on memory CD4+ T cells exhibited significant positive correlation with disease activity in CD, and this decreased significantly after treatment. Such a decrease was not found in the disease controls. CCR5 and CXCR3 expression on memory CD8+ T cells was significantly lower in CD than in normal controls. CXCR3 expression on beta 7(high) memory CD4+ T and CXCR3 expression on memory CD8+ T cells were lower in UC than in normal controls. These findings suggest that in peripheral blood memory T cells, chemokine receptor expression is different between CD and UC. Enhancement of CCR4 and suppression of CCR5 and CXCR3 seem to be the characteristic chemokine receptor profile in peripheral blood memory T cells of CD.
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PMID:CCR4 is an up-regulated chemokine receptor of peripheral blood memory CD4+ T cells in Crohn's disease. 1269 25

The chemokine gene cluster [CCL22, CX3CL1, CCL17] (previously known as [SCYA22, SCYD1, SCYA17]) is a candidate locus for one of the susceptibility genes for inflammatory bowel disease that are located in the peri-centromeric region of chromosome 16. Screening for sequence variation at this locus led to the detection of 14 single nucleotide polymorphisms (SNPs). An efficient experimental and computational approach was developed to estimate allele frequencies and pairwise linkage disequilibrium relationships between SNPs at this locus, and to test them for association with inflammatory bowel disease. The 12 common SNPs were assigned to 5 distinct linkage disequilibrium groups. Genotyping of one SNP from each linkage disequilibrium group in a large cohort of families with inflammatory bowel disease did not provide convincing evidence of association with either Crohn's disease or ulcerative colitis. We describe an efficient experimental design from SNP screening to association testing. This strategy can be used to test candidate genes for involvement in susceptibility to complex disease.
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PMID:Genetic variation at the chromosome 16 chemokine gene cluster: development of a strategy for association studies in complex disease. 1294 Sep 13

Ulcerative colitis (UC) and Crohn's disease (CD), collectively termed inflammatory bowel diseases (IBD), represent chronic relapsing and remitting inflammatory disorders of the gastrointestinal tract that are characterized by leukocytic infiltration of the intestinal mucosa and submucosa. In CD, the inflammation is transmural and frequently associated with granuloma formation. Chemokines have emerged as the most important regulators of leukocyte trafficking during infection or inflammation and, therefore, have been implicated in the pathogenesis of IBD. In this review, recent advances on the role of chemokines and their receptors in mucosal immunity and inflammation are discussed, and the potential use of chemokine/chemokine-receptor antagonists as novel therapeutic targets for the treatment of human IBD is highlighted.
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PMID:Chemokines in inflammatory bowel disease. 1468 Jun 27

The normal gut flora has been implicated in the pathophysiology of inflammatory bowel disease and there is increased interest in the role that stress can play in gut disease. The chemical stressor dinitrophenol (DNP, uncouples oxidative phosphorylation) was injected into the ileum of laparotomized rats and mitochondria structure, epithelial permeability, and inflammatory cell infiltrate were examined 6 and 24 hours later. Monolayers of human colonic epithelial cells (T84, HT-29) were treated with DNP +/- commensal Escherichia coli, followed by assessment of epithelial permeability, bacterial translocation, and chemokine (ie, interleukin-8) synthesis. Delivery of DNP into rat distal ileum resulted in disruption of epithelial mitochondria; similar changes were noted in mildly inflamed ileal resections from patients with Crohn's disease. Also, DNP-treated ileum displayed increased gut permeability and immune cell recruitment. Subsequent studies revealed deceased barrier function, increased bacterial translocation, increased production of interleukin-8, and enhanced mobilization of the transcription factor AP-1 in the model epithelial cell lines exposed to commensal bacteria (E. coli strains HB101 or C25), but only when the monolayers were pretreated with DNP (0.1 mmol/L). These data suggest that enteric epithelia under metabolic stress perceive a normally innocuous bacterium as threatening, resulting in loss of barrier function, increased penetration of bacteria into the mucosa, and increased chemokine synthesis. Such responses could precipitate an inflammatory episode and contribute to existing enteric inflammatory disorders.
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PMID:Epithelia under metabolic stress perceive commensal bacteria as a threat. 1498 48

SAMP1/Yit mice spontaneously develop ileitis resembling Crohn's disease (CD) without chemical or genetic manipulations. Since the focus of studies were Th1 cytokines, only Th1-type T cells were thought to be responsible for intestinal inflammation in these mice. To further characterize the pathogenesis of this ileitis, we investigated the implication of Th2 cytokines in ileitis of SAMP1/Yit mice. The expression of chemokine receptors (CCR) associated with both Th1 and Th2 lymphocytes, such as CCR2, CCR3, CCR4, CCR5, and CCR8, was increased. Among cytokines, IL-5 was remarkably increased in Peyer's patches, mesenteric lymph nodes, and mucosa involved in ileitis. Furthermore, infiltration of numerous eosinophils in ileitis was histologically evident. Severe combined immunodeficiency mice injected intraperitoneally with CD4(+) cells from SAMP1/Yit mice developed colitis and ileitis, with the infiltration of eosinophils. Administration of anti-IL-5 antibodies significantly attenuated ileitis in these mice. We suggest that IL-5 participates in the pathogenesis of ileitis and that anti-IL-5 antibodies are potentially useful for immunotherapy in CD patients. This is the first demonstration that IL-5 is crucial for the development of ileitis in this mouse model of CD.
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PMID:Interleukin-5 participates in the pathogenesis of ileitis in SAMP1/Yit mice. 1516 25

Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD) that are characterized by chronic intestinal inflammation and a constant influx of leukocytes mediated by pro-inflammatory cytokines and chemokines. The intestinal expression of the CXCR1-binding chemokines IL-8/CXCL8 and GCP-2/CXCL6 and the participation of immunocompetent cells in IBD were evaluated. IL-8 production by peripheral blood mononuclear cells (PBMC) from IBD patients, stimulated with endotoxin, plant lectin or double-stranded RNA, was significantly lowered in patients with CD, but not in UC patients or healthy subjects. The reduced chemokine production by PBMC from IBD patients was both IL-8 and CD specific, but not inducer dependent. In serum, most chemokines remained undetectable, while the levels of those that were measurable remained unaltered in IBD patients. GCP-2, but not ENA-78/CXCL5, nor IL-8, were highly expressed by endothelial cells in inflamed intestinal tissue of IBD patients. In contrast, stimulated endothelial cell cultures produced more IL-8 than GCP-2. The selective GCP-2 staining of endothelial cells at sites of ulcerations suggests that GCP-2, despite its low production capacity in vitro, plays a role in IBD that is different from that of structurally (ENA-78) and functionally (IL-8) related ELR(+) CXC chemokines. Thus, the chemokine network shows complementarity rather than redundancy.
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PMID:CXCR1-binding chemokines in inflammatory bowel diseases: down-regulated IL-8/CXCL8 production by leukocytes in Crohn's disease and selective GCP-2/CXCL6 expression in inflamed intestinal tissue. 1521 47

Changes in diet greatly affect the mucosal immune system, particularly in diseases such as Crohn's disease and necrotizing enterocolitis. This review examines the hypothesis that alterations in the luminal environment of the intestine regulate the expression of genes in the epithelium responsible for signaling to immune cells. Increasing chemokine expression in the mouse intestinal epithelium using transgenic techniques enhances the recruitment of neutrophils and lymphocytes into the intestine. Furthermore, SCFA concentrations in the intestinal lumen vary markedly with diet. SCFAs alter chemokine expression by inhibiting histone deacetylase activity in the enterocyte. The review therefore describes a molecular pathway explaining how changes in diet may alter leukocyte recruitment by regulating enterocyte gene expression. It is likely that other similar pathways remain to be discovered.
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PMID:Short chain fatty acid regulation of signaling genes expressed by the intestinal epithelium. 1533 41

Crohn's disease is associated with an excessive T helper (TH) type 1 inflammatory immune response. Reducing the influx of disease-associated CD4+ TH1 cells into the inflamed intestine is likely to be beneficial in preventing a disease flare-up and even possibly in reducing the effect of acute disease. Thiazolidenedione (TZD) ligands, which activate peroxisome proliferator-activated receptor-gamma (PPARgamma), have been shown to reduce TH1 inflammation in murine models of colitis, primarily in a preventative fashion. To determine whether PPARgamma ligands reduce this inflammation in part by reducing TH1 chemoattractant levels in vivo, the TZD pioglitazone was tested for its effects on a TH1 chemokine (CXCL10) in 2 models of colitis (i.e., dextran sodium sulfate and 2,4,6-dinitrobenzene sulfonic acid-mediated colitis). In both models, CXCL10 levels were significantly reduced by pioglitazone. Because TZDs can affect gene expression either directly, by regulating the binding of PPARgamma to consensus promoter elements, or indirectly, by modulating other signaling pathways that can affect gene transcription, the regulation of CXCL10 by TZDs was investigated in vitro in both HT-29 colon epithelial cells and THP-1 monocyte/macrophage cells. TZDs significantly reduced CXCL10 protein levels from activated HT-29 cells and THP-1-derived macrophages in a dose-dependent manner at nanomolar concentrations. However, TZDs did not affect messenger RNA levels or nuclear factor-kappaB activation at these concentrations in these cells. These findings imply the existence of a novel posttranscriptional regulatory antiinflammatory mechanism by TZDs that is not associated with reductions in nuclear factor-kappaB activation.
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PMID:Intestinal antiinflammatory effects of thiazolidenedione peroxisome proliferator-activated receptor-gamma ligands on T helper type 1 chemokine regulation include nontranscriptional control mechanisms. 1573 30


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