Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage migration inhibitory factor (MIF) is a cytokine that has potent anti-steroid effects and might be implicated in the pathogenesis of Ulecrative colitis (UC). We defined the functional role of MIF in the glucocorticoid (GC)-resistant inflammatory response in UC. Twenty-four colonic samples were obtained from GC responsive cases, GC refractory cases, Crohn's disease and controls. LPMC were isolated from surgical specimens. MIF was strongly expressed at mRNA levels in refractory cases rather than responsive cases with UC and controls. IL-8 production from LPMC was significantly reduced by GC addition in responsive cases but not in refractory cases. In refractory cases, anti-MIF Ab ameliorated GC-resistant IL-8 production and p38-MAPK activity of LPMC. In addition, p38-MAPK antagonist SB230580 also ameliorated GC-resistant IL-8 production. These results suggest that MIF has an additional proinflammatory activity through the p38-MAPK pathway in GC-resistant UC.
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PMID:Macrophage migration inhibitory factor has a proinflammatory activity via the p38 pathway in glucocorticoid-resistant ulcerative colitis. 1680 15

Crohn disease and ulcerative colitis are caused by an excessive immune-inflammatory reaction in the intestinal wall. Analysis of the types of immune response ongoing in the inflamed intestine has revealed that in Crohn disease there is predominantly a T helper cell type 1 response, with exaggerated production of interleukin (IL)-12 and interferon-gamma, whereas in ulcerative colitis the lesion seems to be more of an antibody-mediated hypersensitivity reaction. Despite these differences, downstream inflammatory events are probably similar in both conditions. In both Crohn disease and ulcerative colitis there is an increased synthesis of proinflammatory cytokines, including IL-1beta, IL-6, IL-8, IL-16, and tumor necrosis factor-alpha accompanying the influx of nonspecific inflammatory cells into the mucosa. These cytokines contribute to the tissue damage either directly or indirectly by enhancing the production of matrix metalloproteinases and growth factors, which produce ulceration as well as mucosal repair.
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PMID:Mechanisms of tissue damage in inflammatory bowel disease. 1703 Nov 75

Carrageenan is a high molecular weight sulfated polygalactan used to improve the texture of commercial food products. Its use increased markedly during the last half century, although carrageenan is known to induce inflammation in rheumatological models and in intestinal models of colitis. We performed studies to determine its direct effects on human intestinal cells, including normal human intestinal epithelial cells from colonic surgeries, the normal intestinal epithelial cell line NCM460, and normal rat ileal epithelial cells. Cells were treated with high molecular weight lambda-carrageenan at a concentration of 1 mug/ml for 1-96 h. IL-8, IL-8 promoter activity, total and nuclear NF-kappaB, IkappaBalpha, phospho-IkappaBalpha, and Bcl10 were assessed by immunohistochemistry, Western blot, ELISA, and cDNA microarray. Increased Bcl10, nuclear and cytoplasmic NF-kappaB, IL-8 promoter activation, and IL-8 secretion were detected following carrageenan exposure. Knockdown of Bcl10 by siRNA markedly reduced the increase in IL-8 that followed carrageenan exposure in the NCM460 cells. These results show, for the first time, that exposure of human intestinal epithelial cells to carrageenan triggers a distinct inflammatory pathway via activation of Bcl10 with NF-kappaB activation and upregulation of IL-8 secretion. Since Bcl10 contains a caspase-recruitment domain, similar to that found in NOD2/CARD15 and associated with genetic predisposition to Crohn's disease, the study findings may represent a link between genetic and environmental etiologies of inflammatory bowel disease. Because of the high use of carrageenan as a food additive in the diet, the findings may have clinical significance.
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PMID:Carrageenan induces interleukin-8 production through distinct Bcl10 pathway in normal human colonic epithelial cells. 1709 57

Ulcerative colitis (UC) and Crohn's disease (CD) are the major forms of idiopathic inflammatory bowel disease (IBD). Both UC and CD are debilitating chronic disorders that afflict millions of individuals throughout the world with symptoms which impair function and quality of life. The etiology of IBD is inadequately understood and therefore, drug therapy has been empirical instead of being based on sound understanding of IBD pathogenesis. This is a major factor for poor drug efficacy and drug related side effects that often add to the disease complexity. The development of biologicals notably infliximab to intercept tumor necrosis factor (TNF)-alpha reflects some progress, albeit major concern about their side effects and lack of long-term safety and efficacy profiles. However, IBD seems to be perpetuated by inflammatory cytokines like TNF-alpha, interleukin (IL)-1beta, IL-6 and IL-8 for which activated peripheral granulocytes and monocytes/macrophages (GM) are major sources. Further, in IBD, peripheral GMs are elevated with activation behavior, increased survival time and are found in vast numbers within the inflamed intestinal mucosa; they are suspected to be major factors in the immunopathogenesis of IBD. Hence, peripheral blood GMs should be appropriate targets of therapy. The Adacolumn is a medical device developed for selective depletion of GM by receptor-mediated adsorption (GMA). Clinical data show GMA, in patients with steroid dependent or steroid refractory UC, is associated with up to 85% efficacy and tapering or discontinuation of steroids, while in steroid naive patients (the best responders), GMA spares patients from exposure to steroids. Likewise, GMA at appropriate intervals in patients at a high risk of clinical relapse suppresses relapse thus sparing the patients from the morbidity associated with IBD relapse. Further, GMA appears to reduce the number of patients being submitted to colectomy or exposure to unsafe immunosupressants. First UC episode, steroid naivety and short disease duration appear good predictors of response to GMA and based on the available data, GMA seems to have an excellent safety profile.
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PMID:Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis. 1717 83

Elafin (or skin-derived antileukoprotease) and secretory leukocyte protease inhibitor (SLPI) are serine antiproteases antagonizing human neutrophil elastase (HNE), thereby preventing tissue injury from excessive release of proteolytic enzymes by inflammatory cells. Furthermore, elafin and SLPI are "defensin-like" molecules with broad antimicrobial activity. The balance between proteases and antagonists may critically determine inflammatory processes in Crohn's disease (CD) and ulcerative colitis (UC). Real-time PCR was performed to quantitate colonic, proinflammatory cytokine IL-8, protease (HNE), and antiprotease mRNA (elafin and SLPI) in a total of 340 biopsies from 117 patients (47 CD, 45 UC, 25 controls). Histological inflammation was scored, and HNE, elafin, and SLPI were localized and semiquantified by immunostaining in 51 colonic paraffin sections (23 CD, 11 UC, 17 controls). Proinflammatory IL-8, degree of histological inflammation, and granulocyte content were similar in UC and CD. Elafin stained predominantly in the epithelium and SLPI in mucosal inflammatory cells. HNE mRNA levels and immunostaining were increased equally in both forms of inflammatory bowel disease. Levels of mRNA and immunostaining of the antiproteases elafin and SLPI were enhanced strongly in inflamed versus noninflamed UC. It is surprising that comparing inflamed versus noninflamed CD, this increase was significantly less pronounced for elafin and even lacking for SLPI. Despite comparable degrees of inflammation and protease levels, the induction of both antiproteases was attenuated in CD. This could contribute to the transmural depth of tissue destruction in CD. Elafin and SLPI may be added to the list of defensin-like peptides with diminished induction in CD versus UC.
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PMID:Attenuated induction of epithelial and leukocyte serine antiproteases elafin and secretory leukocyte protease inhibitor in Crohn's disease. 1720 Jan 45

Exclusive enteral nutrition using polymeric formula (PF) is a well-established therapeutic option for active Crohn's disease; however, its mechanisms of action are unknown. We investigated the anti-inflammatory effects of PF in an in vitro model of epithelial cell inflammation. PF did not affect cell viability over a range of dilutions, but when PF was added to the culture medium the interleukin (IL)-8 response to proinflammatory stimuli was significantly reduced. This effect was due to PF acting directly on the cells as the IL-8 response was still reduced when PF was separated from the proinflammatory stimuli in a 2-compartment system. In the presence of PF, nuclear factor (NF)-kappaB nuclear migration was not inhibited; however, IkappaBalpha degradation was delayed. PF has direct anti-inflammatory effects upon immortalized colonic enterocytes. Therefore PF may, in part, modulate gut inflammation by directly reducing the inflammatory response of the intestinal epithelium.
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PMID:Polymeric formula has direct anti-inflammatory effects on enterocytes in an in vitro model of intestinal inflammation. 1740 42

Increased numbers of mucosa-associated Escherichia coli are observed in both major inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC). With the identification of mutations in the NOD2-encoding gene in patients with CD and given the intracellular location of NOD2, the presence of pathogenic invasive bacteria could be the link between innate immune response to invasive bacteria and the development of the inflammation. Adherent-invasive E. coli (AIEC) are isolated from ileal biopsies of 36.4% of patients with ileal involvement of CD. These pathogenic E. coli colonize the intestinal mucosa by adhering to intestinal epithelial cells and are also true invasive pathogens, able to invade intestinal epithelial cells and to replicate intracellularly. AIEC strains also survive and replicate extensively within macrophages without inducing host cell death, and their high replication rates induce the secretion of large amounts of tumor necrosis factor alpha (TNF-alpha). There is also evidence suggesting that AIEC is involved in the formation of granulomas. The presence of AIEC is restricted to CD patients. Mucosa-associated E. coli in patients with UC can adhere to intestinal epithelial cells and induce the secretion of IL-8, but there is no evidence that these E. coli strains are invasive.
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PMID:Adherent-invasive Escherichia coli in inflammatory bowel disease. 1747 74

Caspase activation and recruitment domain 15 (CARD15) and Toll-like receptor 4 (TLR4) are respectively intracellular and membrane-bound receptors for bacterial cell wall components [respectively muramyl dipeptide (MDP) and lipopolysaccharide (LPS)]. Polymorphisms in CARD15 and TLR4 have been linked with Crohn's disease (CD). Adherent-invasive Escherichia coli (AIEC) strains with particular adhesion and invasion characteristics have been specifically associated with CD ileal mucosa. The aim of this study was to investigate the functional impact of these polymorphisms on monocytes in patients with CD, in response to MDP, LPS and AIEC strain LF82. Monocytes were isolated from 40 patients with CD using magnetic cell sorting, stimulated with LPS or MDP or infected with AIEC. IL-1beta, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor alpha induction was assessed using quantitative real time-polymerase chain reaction, Cytometric Bead Array and ELISA. Bacterial intracellular survival and replication was assessed using a gentamicin protection assay. Results were linked with the presence of CARD15 and TLR4 polymorphisms. Monocytes of patients with CARD15 polymorphisms showed an early reduced cytokine response (IL-1beta, IL-6 and IL-10) to infection with AIEC, which was restored after 20 h. A gene-dose effect was seen, comparing wild-types, heterozygotes and homozygotes. We found no differences in intracellular survival and replication of AIEC. Heterozygous carriage of TLR4 polymorphisms did not influence monocyte response. In conclusion, patients with CD carrying CARD15 polymorphisms show a disturbed early inflammatory monocyte response after infection with AIEC strain LF82. For the first time, a functional defect was detected in single heterozygous carriers. These findings reflect the potential role of a genetically altered host response to disease-related bacteria in the pathogenesis of CD.
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PMID:CARD15 variants determine a disturbed early response of monocytes to adherent-invasive Escherichia coli strain LF82 in Crohn's disease. 1750 8

Crohn's disease (CD) and ulcerative colitis (UC) are idiopathic inflammatory conditions of the gut. Our goal was to investigate if invasive Escherichia coli strains were present in patients with inflammatory bowel disease (IBD). Bacterial strains were isolated from biopsy material obtained from normal controls, and patients with a clinical diagnosis of CD and UC. Invasive bacteria were characterized by gentamicin protection assay and biochemical profiling (Api-20E). Strains were characterized by induction of cytokine expression in epithelial and macrophage cell cultures, measurement of epithelial barrier function, and confocal microscopy. Of all invasive bacterial strains in CD 98.9% were identified as E. coli as opposed to 42.1% in UC and 2.1% in normal controls. Epithelial invasion in vitro was significantly higher for CD-associated E. coli (8.4%, +/-5.5 of initial inoculum (I/O)) in comparison to UC (2.5%, +/-0.4 I/O), but highest for strains from inflamed CD tissue (11.3%, +/-4.3 I/O). Both, CD and UC E. coli strains induced high mean TNF-alpha expression in macrophage cell lines (2604.8 pg/10(5) cells, +/-447.4; 2,402.6 pg/10(5) cells, +/-476.3, respectively), but concentrations were significantly higher for isolates from inflamed CD tissue (3071.3 pg/10(5) cells, +/-226.0). Invasive E. coli from IBD tissue induced similar concentrations of interleukin (IL)-8 in epithelial cell cultures, but strains from inflamed CD tissue induced significantly less epithelial IL-8 (674.1 pg/10(5) cells, +/-58.0 vs 920.5 pg/10(5) cells, +/-94.6). IBD-associated E. coli strains significantly decreased transepithelial resistance, induced disorganization of F-actin and displacement of ZO-1, and E-cadherin from the apical junctional complex (AJC). In comparison to normal controls and UC, E. coli are more prevalent in CD, are highly invasive, and do not encode for known effector proteins. E. coli strains from IBD patients regulate cytokine expression and epithelial barrier function, two pathological features of IBD.
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PMID:Invasive Escherichia coli are a feature of Crohn's disease. 1808 52

Changes in diet greatly affect the mucosal immune system, particularly in diseases such as Crohn's disease and necrotizing enterocolitis. This article examines the hypothesis that alterations in the luminal environment of the intestine regulate the expression of genes in the enterocyte responsible for signaling to immune cells. Genes expressed by the epithelium orchestrate leukocytes in the lamina propria. For example, chemokine expression in the mouse intestinal epithelium, through transgenic means, induced the recruitment of neutrophils and lymphocytes into intestinal tissues. Diet alters the expression of the genes responsible for signaling by a variety of pathways. The introduction of a normal diet to a weanling mouse up-regulates MHC class II expression through a particular isoform of the class II transactivator, a protein that acts in the nucleus. SCFA concentrations in the intestinal lumen vary markedly with diet. SCFAs increase IL-8 and insulin-like growth factor binding protein-2 expression by inhibiting histone deacetylase activity in the enterocyte. Down-regulation of gene expression by butyrate can act through acetylation of the inhibitory transcription factor Sp3. The review therefore describes a number of molecular pathways, explaining how changes in diet may alter leukocyte recruitment by regulating enterocyte gene expression. Myofibroblasts enhance enterocyte chemotactic activity by cleaving inactive precursors; and myofibroblast genes also are regulated by SCFA. It is likely that other similar regulatory mechanisms remain to be discovered.
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PMID:Dietary modulation of GALT. 1795 2


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