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)

alpha(2A)-adrenoceptors are expressed on intestinal cells and they participate in the control of epithelial functions such as solute and water transport or cell proliferation. In pathological conditions, pro-inflammatory cytokines secreted by lymphocytes are responsible for modification of intestinal cell characteristics including phenotype switch and changes in the expression of pumps and ion channels. Using the HT29 cell line as a model, the present work examined the effect of two inflammatory cytokines, interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha), on the expression of the human alpha(2A)-adrenoceptor. Exposure of cells to either IFNgamma or TNFalpha resulted in a concentration- and time-dependent diminution of [(3)H]RX821002 binding sites, which is preceded by a large decrease in the amount of alpha(2A)-adrenoceptor mRNA. The cytokines did not affect the receptor mRNA half-life, but inhibited the activity of a luciferase construct containing the promoter region of alpha(2A)-adrenoceptor gene, indicating that a decrease in the transcription rate is primarily responsible for the diminution of receptor expression. Exposure of cells to either IFNgamma or TNFalpha caused increased production of reactive oxygen species and transient phosphorylation of extracellular signal-regulated kinase (Erk1/2). The effect of cytokines was mimicked by H(2)O(2) but was unaffected by the addition of anti-oxidants. The blockade of Erk1/2 activation by PD98059 blunted the effect of TNFalpha but not of IFNgamma. In conclusion, the present findings demonstrate that IFNgamma and TNFalpha diminish the alpha(2A)-adrenoceptor expression in HT29 cells by decreasing the transcription rate without modifying the stability of mRNA. The transcription inhibition is however triggered via different signalling pathways. The results suggest that cytokine-mediated down-regulation of alpha(2A)-adrenoceptor could contribute to the pathogenesis of inflammatory bowel disease.
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PMID:Transcriptional down-regulation of human alpha(2A)-adrenoceptors by IFNgamma and TNFalpha in intestinal cells. 1845 28

Apart from genetic and environmental factors, the mucosal immune system of the gut plays a central role in the pathogenesis of inflammatory bowel disease (IBD). In the healthy gut, the mucosal immune system ensures the balance between pro- and anti-inflammatory mediators and thereby allows an effective defence against luminal pathogens but at the same time prevents an overwhelming immune reaction directed against the huge amount of harmless luminal antigens (for example, components of food or nonpathological bacteria). In both entities of IBD (Crohn's disease and ulcerative colitis) this immunological balance is severely impaired and shifted towards the pro-inflammatory side. The chronic mucosal inflammation in IBD is caused by hyperactivation of effector immune cells, which produce high levels of pro-inflammatory cytokines like tumour necrosis factor-alpha, interleukin-6 and interferon-gamma, resulting in colonic tissue damage. The nuclear transcription factor kappaB (NF-kappaB) was identified as one of the key regulators in this immunological setting. Its activation is markedly induced in IBD patients and through its ability to promote the expression of various pro-inflammatory genes, NF-kappaB strongly influences the course of mucosal inflammation. Considering the different cell-type specific effects which are mediated by NF-kappaB, this review aims at describing the complex role of NF-kappaB in IBD and discusses existing pharmacological attempts to block the activation of NF-kappaB to develop new therapeutic strategies in IBD.
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PMID:NF-kappaB in inflammatory bowel disease. 1847 58

Recent studies indicate that the CXCL12/CXCR4 interaction is involved in several inflammatory conditions. However, it is unclear whether this interaction has a role in the pathophysiology of inflammatory bowel disease (IBD). We investigated the significance of this interaction in patients with IBD and in mice with dextran sulfate sodium (DSS)-induced colitis and the effect of a CXCR4 antagonist on experimental colitis. First, we measured CXCR4 expression on peripheral T cells in patients with IBD. Furthermore, we investigated CXCR4 expression on leukocytes and CXCL12 expression in the colonic tissue of mice with DSS-induced colitis, and we evaluated the effects of a CXCR4 antagonist on DSS-induced colitis and colonic inflammation of interleukin (IL)-10 knockout (KO) mice. Colonic inflammation was assessed both clinically and histologically. Cytokine production from mesenteric lymph node cells was also examined. CXCR4 expression on peripheral T cells was significantly higher in patients with active ulcerative colitis (UC) compared with normal controls, and CXCR4 expression levels of UC patients correlated with disease activity. Both CXCR4 expression on leukocytes and CXCL12 expression in colonic tissue were significantly increased in mice with DSS-induced colitis. Administration of a CXCR4 antagonist ameliorated colonic inflammation in DSS-induced colitis and IL-10 KO mice. CXCR4 antagonist reduced tumor necrosis factor-alpha and interferon-gamma production from mesenteric lymph node cells, whereas it did not affect IL-10 production. The percentage of mesenteric Foxp3+CD25+ T cells in DSS-induced colitis was not affected by CXCR4 antagonist. These results suggest that blockade of this chemokine axis might have potential as a therapeutic target for the treatment of IBD.
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PMID:Blockade of CXCL12/CXCR4 axis ameliorates murine experimental colitis. 1871 65

The normal intestinal flora is required for the development of intestinal inflammation in animal models of inflammatory bowel disease (IBD). In humans, several studies indicated a potential association of Escherichia coli (E. coli) with IBD. In addition, we have shown that T-cell clones of IBD patients cross react toward different enteric bacterial species and thus likely respond to conserved bacterial antigens. Therefore, we hypothesized that highly conserved E. coli proteins might be a reasonable candidate to screen for abnormal T-cell responses in IBD. We used high-throughput techniques for cloning, expression, and purification under native conditions of a set of 271 conserved proteins of E. coli, of which 196 were used for whole blood stimulations to assess peripheral T helper (T(H))-cell responses. In addition, because of the association of an adherent-invasive E. coli with Crohn's disease (CD), we included 13 pathogenicity factors of E. coli in the study. We observed that pools of these conserved E. coli proteins less frequently induced interferon-gamma (IFNgamma) production in peripheral T(H) cells in patients with CD and ankylosing spondylitis (AS) compared with healthy controls. In addition, lower percentage of patients with CD and AS responded toward single proteins. The reason for the decreased frequency of an in vitro T(H)-cell IFNgamma response toward E. coli proteins in peripheral blood of CD and AS patients, e.g., increased suppression needs to be clarified.
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PMID:Identification of the predominant antigenic epitopes in intestinal flora in IBD. 1907 22

Guanylate-binding protein-1 (GBP-1) is an interferon inducible large GTPase involved in endothelial cell proliferation and invasion. In this report, expression and function of GBP-1 were investigated in vitro in intestinal epithelia after exposure to interferon-gamma and in human colonic mucosa from individuals with inflammatory bowel disease (IBD). Interestingly, in contrast to other epithelia, GBP-1 distributed to the plasma membrane in intestinal epithelial cells where it colocalized with the tight junction protein coxsackie- and adenovirus receptor. In addition, expression of GBP-1 was upregulated in colonic epithelia of individuals with IBD. Downregulation of GBP-1 by siRNA resulted in enhanced permeability that correlated with increased apoptosis. Indeed, inhibition of caspase activity prevented the inhibition of barrier formation induced by the loss of GBP-1. These data suggest that GBP-1 is a novel marker of intestinal mucosal inflammation that may protect against epithelial apoptosis induced by inflammatory cytokines and subsequent loss of barrier function.
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PMID:Guanylate-binding protein-1 is expressed at tight junctions of intestinal epithelial cells in response to interferon-gamma and regulates barrier function through effects on apoptosis. 1907 32

Protracted inflammation leading to dysregulation of effector T-cell responses represents a common feature of a wide range of autoimmune diseases. The interleukin-12 (IL-12)/T-helper 1 (Th1) pathway was thought to be responsible for the pathogenesis of multiple chronic inflammatory diseases, including psoriasis, inflammatory bowel disease, arthritis, or multiple sclerosis, mainly through their production of interferon-gamma and its effects on macrophage activation and chemokine production. However, this initial concept of T-cell-mediated chronic inflammation required an adjustment with the discovery of an IL-12-related cytokine, designated IL-23. IL-23 was rapidly recognized for its involvement in the establishment of chronic inflammation and in the development of a Th cell subset producing IL-17, designated Th17, which is distinct from the previously reported Th1 and Th2 populations. This review aims to describe the characterization of IL-23 and its receptor, its biological activities, as well as its involvement in the development of human Th17 cells and autoimmunity.
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PMID:From interleukin-23 to T-helper 17 cells: human T-helper cell differentiation revisited. 1916 21

Intestinal epithelial cells (IECs) play a key role in Crohn's disease, a chronic inflammatory bowel disease which requires invasive examinations to be diagnosed. The comparison of the cellular protein expression profiles of Crohn's disease patients and healthy subjects is fundamental for the identification of proteins clinically relevant as new biomarkers or as drug targets. For this purpose a differential label-free nano-LC ESI/QTOF mass spectrometry (MS) approach combined with targeted MS/MS analysis has been developed and applied to isolated IECs. We report here a study of the protein variations in IECs from healthy subjects (H) and Crohn's disease patients (CD). The method was previously validated using HT29 Cl.16E cell line, normal or treated with interferon-gamma as a model of inflammation. Subcellular fractions proteins were extracted from HT29 and IECs and for each fraction monodimensional gel-electrophoresis was performed and the proteins subjected to tryptic digestion. The resulting peptides were analysed by LC ESI/QTOF MS and the obtained chromatographic runs were aligned with msInspect software. The peptides differently expressed were statistically evaluated using the Proteios Software Environment (ProSE) and identified by LC ESI/QTOF MS/MS analysis and database search. The preliminary results obtained allowed the identification of many proteins involved in the inflammation processes.
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PMID:Differential proteomic analysis of HT29 Cl.16E and intestinal epithelial cells by LC ESI/QTOF mass spectrometry. 1916 59

Tyrosine kinase (TK)-mediated phosphorylation regulates signal transduction pathways resulting in the expression of a variety of inflammatory genes. Inhibition of TK activity in vivo has been shown to increase survival in a lethal model of murine endotoxemia, suggesting a novel therapeutic approach to inflammation and circulatory shock. We examined the role of TK activity on the expression of the inducible nitric oxide (NO) synthase (iNOS). Under resting conditions, iNOS is not expressed in human cells. In response to various proinflammatory stimuli, however, iNOS expression is upregulated, resulting in high-output NO synthesis. iNOS-derived NO plays a critical role as a cytotoxic effector species and has been implicated in the pathogenesis of many clinical inflammatory conditions, including inflammatory bowel disease, arthritis, transplant rejection, diabetes, and sepsis. We examined the signaling pathways governing iNOS expression in monolayers of DLD-1 cells, a human epithelial cell line derived from an intestinal adenocarcinoma. Induction of iNOS transcription in interferon-gamma-primed cells by treatment with lipopolysaccharide, Salmonella sp., or interleukin-1beta was potently inhibited by pretreatment with genistein, an isoflavone derived from the soy species genistin. Other isoflavones, such as genistin, daidzein, and daidzin, were not inhibitory. TK inhibition by genistein had no effect on the expression or nuclear translocation of the transcription factors interferon regulatory factor-1 and nuclear factor-KB, respectively, both of which have been implicated in transcriptional regulation of the human iNOS gene. Nuclear run-on analysis demonstrated that the effect of genistein on iNOS messenger RNA expression was not at the level of transcription, suggesting that posttranscriptional regulation of iNOS messenger RNA might be TK dependent. Isoflavones, such as genistein, are useful tools to dissect regulatory pathways in vitro and in vivo and may have potential use as novel antiinflammatory therapeutic agents.
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PMID:Isoflavone-mediated inhibition of tyrosine kinase: a novel antiinflammatory approach. 1928 74

Inflammatory bowel disease (IBD) is chronic inflammatory and relapsing disease of the gut. It has been known that activation of nuclear factor-kappaB (NF-kappaB) and production of proinflammatory cytokines play important roles in the pathogenesis of IBD. In this study, the effect of vanillin (4-hydroxy-3-methoxybenzaldehyde), a potent nuclear factor-kappaB (NF-kappaB) inhibitor, was evaluated in mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis. Oral administration of vanillin improved macroscopic and histological features of TNBS-induced colitis in a dose-dependent manner. Vanillin not only prevented TNBS-induced colitis but also ameliorated the established colitis. By in vivo NF-kappaB bioluminescence imaging, electrophoretic mobility shift assay, and Western blot, we found that vanillin suppressed in vivo NF-kappaB activities through the inhibition of p65 translocation, inhibitor of nuclear factor-kappaB(IkappaB)-alpha phosphorylation, and IkappaB kinase activation. Furthermore, vanillin reduced the expressions of proinflammatory cytokines [interleukin (IL)-1beta, IL-6, interferon-gamma, and tumor necrosis factor-alpha] and stimulated the expression of anti-inflammatory cytokine (IL-4) in colonic tissues. In conclusion, this work identified vanillin as an anti-inflammatory compound with the capacity to prevent and ameliorate TNBS-induced colitis. Due to its safety, vanillin could be a potent candidate for the treatment of IBD.
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PMID:Vanillin improves and prevents trinitrobenzene sulfonic acid-induced colitis in mice. 1942 42

The aim of this study was to examine the efficacy of in ovo prime-boost vaccination against infectious bursal disease virus (IBDV) using a DNA vaccine to prime in ovo followed by a killed-vaccine boost post hatching. In addition, the adjuvant effects of plasmid-encoded chicken interleukin-2 and chicken interferon-gamma were tested in conjunction with the vaccine. A plasmid DNA vaccine (pcDNA-VP243) encoding the VP2, VP4, and VP3 proteins of the very virulent IBDV (vvIBDV) SH/92 strain was injected into the amniotic sac alone or in combination with a plasmid encoding chicken IL-2 (ChIL-2) or chicken IFN-gamma (ChIFN-gamma) at embryonation day 18, followed by an intramuscular injection of a commercial killed IBD vaccine at 1 week of age. The chickens were orally challenged with the vvIBDV SH/92 strain at 3 weeks of age and observed for 10 days. In ovo DNA immunization followed by a killedvaccine boost provided significantly better immunity than the other options. No mortality was observed in this group after a challenge with the vvIBDV. The prime-boost strategy was moderately effective against bursal damage, which was measured by the bursa weight/body weight ratio, the presence of IBDV RNA, and the bursal lesion score. In ovo DNA vaccination with no boost did not provide sufficient immunity, and the addition of ChIL-2 or ChIFN-gamma did not enhance protective immunity. In the ConA-induced lymphocyte proliferation assay of peripheral blood lymphocyte collected 10 days post-challenge, there was greater proliferation responses in the DNA vaccine plus boost and DNA vaccine with ChIL-2 plus boost groups compared to the other groups. These findings suggest that priming with DNA vaccine and boosting with killed vaccine is an effective strategy for protecting chickens against vvIBDV.
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PMID:Protection of chicken against very virulent IBDV provided by in ovo priming with DNA vaccine and boosting with killed vaccine and the adjuvant effects of plasmid-encoded chicken interleukin-2 and interferon-gamma. 1946 Dec 8


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