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)

Proinflammatory cytokines are believed to be involved in the pathogenesis of ulcerative colitis (UC). The aim of this study was to clarify the profiles of proinflammatory cytokine production in patients with UC in terms of disease intractability, endoscopic findings, and host response to lipopolysaccharide (LPS) stimulation. Colonic mucosal tissues were obtained from patients with active UC (n = 15, including 4 patients with intractable disease) and inactive UC (n = 7), non-inflammatory bowel disease (IBD) colitis (n = 11), and controls (n = 20). Organ culture was performed, and the amounts of four cytokines (described below) in the culture media were determined by enzyme-linked immunosorbent assay (ELISA). LPS stimulation enhanced interleukin (IL)-1beta, IL-8, and IL-6 production in colonic specimens from all groups, but enhanced tumor necrosis factor (TNF)-alpha production only in active UC specimens. Levels of IL-6, IL-8, and TNF-alpha were significantly higher in active UC than in non-IBD colitis, and the production of all three of these cytokines was correlated to the endoscopic grade of inflammation. The production of these cytokines was also significantly higher in patients with intractable disease receiving corticosteroids than in patients with non-intractable disease receiving corticosteroids. These results suggest that enhanced production of mucosal proinflammatory cytokines may be implicated in the pathogenesis of UC.
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PMID:Mucosal proinflammatory cytokine production correlates with endoscopic activity of ulcerative colitis. 1020 29

Anecdotal reports suggest that smoking may be beneficial for patients with inflammatory bowel disease (IBD) as nicotine may act through inflammatory mediators within the colonic mucosa. Furthermore, there is increasing evidence that cytokines play a pathologic role in IBD. Our aim was to determine the effects of cigarette smoking on cytokine levels in the colonic mucosa of patients with and without IBD. Mucosal biopsies were obtained from 10 patients with Crohn's disease (CD), 10 with ulcerative colitis (UC), and 10 healthy controls. Five of 10 patients in each of the three groups were smokers and five were nonsmokers. Concentrations of interleukin (IL)-1beta, IL-2, IL-6, and IL-8 were determined using enzyme-linked immunosorbent assay (ELISA). Cytokine levels of smokers were compared with nonsmokers in each group and with controls. Results were analyzed using the Mann-Whitney test; significance was set at p<0.05. The concentration of IL-8 was significantly higher in healthy controls who smoke compared with nonsmokers and significantly reduced in smokers with CD compared with nonsmokers with CD. Moreover, concentrations of IL-1beta and IL-8 were significantly reduced in smokers with UC compared with nonsmokers with UC. Smokers had significantly elevated levels of IL-8 in the colonic mucosa. Smokers with IBD had a significant reduction in cytokine levels; specifically, IL-1beta and IL-8 for patients with UC and IL-8 for patients with CD. Further studies are warranted to determine if this reduction in cytokine levels is histologically and clinically significant.
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PMID:The influence of cigarette smoking on cytokine levels in patients with inflammatory bowel disease. 1033 74

Ulcerative colitis and Crohn's disease are characterized by chronic intestinal inflammation. Intestinal bacteria initiate the activation of intestinal inflammatory processes, which are mediated by proinflammatory cytokines and chemokines. In inflammatory bowel disease, intestinal inflammation is not downregulated, in part due to defective or absent inhibitory processes. Studies to date have demonstrated that IL-8, MCP-1, and ENA-78 are highly expressed in the intestinal mucosa in areas of active Crohn's disease and ulcerative colitis. Neutrophils and macrophages in the inflamed intestine synthesize and secrete large amounts of chemokines in patients with inflammatory bowel disease. Increased chemokine expression has also been observed in epithelial cells, endothelial cells, and smooth muscle cells. Future trials of specific agents capable of inhibiting chemokine synthesis and secretion or blocking chemokine-chemokine receptor interaction will be important to study in patients with ulcerative colitis and Crohn's disease.
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PMID:Chemokines in the inflammatory bowel diseases. 1053 2

Assessment of disease activity in inflammatory bowel disease (IBD), i.e., ulcerative colitis (UC) and Crohn's disease (CD), is done using clinical parameters and various biological disease markers. Ideally, a disease marker must: be able to identify individuals at risk of a given disorder, be disease specific, mirror the disease activity and, finally, be easily applicable for routine clinical purposes. However, no such disease markers have yet been identified for IBD. In this article, classical disease markers including erythrocyte sedimentation rate, acute phase proteins (especially orosomucoid and CRP), leukocyte and platelet counts, albumin, neopterin, and beta2-microglobulin will be reviewed together with emerging disease markers such as antibodies of the ANCA/ASCA type, cytokines (e.g., IL-1, IL-2Ralpha, IL-6, IL-8, TNF-alpha, and TNF-alpha receptors) and with various adhesion molecules. It is concluded that none of the pertinent laboratory surrogate markers of disease activity in IBD are specific or sensitive enough to replace basic clinical observation such as the number of daily bowel movements, general well-being, and other parameters in parallel. Further studies are highly warranted to identify and assess the clinical importance and applicability of new laboratory markers for the diagnosis or the disease activity of IBD.
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PMID:Established and emerging biological activity markers of inflammatory bowel disease. 1092 11

Macrophages are important in the host's immunological and inflammatory responses. There is a large population of these cells in the normal intestinal mucosa where they represent the major antigen presenting cell population capable of determining the type of T cell responses that develop to luminal antigens. Studies suggest that the normal intestinal macrophages cannot be easily induced to mediate acute inflammatory responses. In active inflammatory bowel disease there is an increase in the mucosal macrophage population, derived from circulating monocytes. These recruited macrophages are phenotypically different from the resident population of cells and play a major role in mediating the chronic mucosal inflammation seen in patients with ulcerative colitis and Crohn's disease. They secrete many cytokines that are important in the proinflammatory responses, such as interleukin (IL)-1, IL-6, IL-8, IL-12, IL-18, and tumor necrosis factor-alpha. They also release reactive metabolites of oxygen and nitrogen and proteases that degrade the extracellular matrix. Macrophages also appear to be important during resolution of inflammation and repair of the intestinal mucosa that occurs during disease remission.
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PMID:The key role of macrophages in the immunopathogenesis of inflammatory bowel disease. 1070 Nov 46

This study was conducted to investigate the efficacy of rebamipide against experimental colitis induced by dextran sulfate sodium (DSS) in a rat model of inflammatory bowel disease. Experimental colitis was induced in male Wistar rats by oral administration of 3% DSS solution for one week. The rats were provided with standard diet containing 0.105% rebamipide (160 mg/kg/day) for 1 week. In rats treated with rebamipide, clinical (body weight loss, bloody diarrhea, reduced physical activity, severe anemia, shortened colonic length, and perianal injury) and histopathological (pathological lesion score) findings of DSS colitis were significantly less than in rats with DSS colitis not treated with rebamipide. Rebamipide thus inhibited the induction of colitis. Rebamipide significantly reduced concentrations of both interleukin-1alpha and GRO/CINC-1 (IL-8-like substance) and cell infiltrates in colonic wall, in parallel with decreased activity of myeloperoxidase. It also reduced expression of IL-1 mRNA but did not influence expression of GRO/CINC-1 mRNA. The attenuation of colonic indices of colitis by rebamipide in this rat model suggests that this drug might have beneficial effects in the treatment of human ulcerative colitis. These effects of rebamipide are attributable to its inhibition of inflammatory cytokine-mediated granulocyte (neutrophil) infiltration into the colon.
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PMID:Rebamipide, an antiulcer drug, prevents DSS-induced colitis formation in rats. 1100 13

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPARalpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPARgamma is predominantly expressed in intestine and adipose tissue. PPARgamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARalpha and PPARgamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPARalpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPARgamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPARalpha in inflammation control came from the demonstration that PPARalpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPARalpha deficiency results in a reduced beta-oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNFalpha and metalloproteases) by negatively interfering with the NF- kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.
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PMID:Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. 1108

In recent years, new concepts have been formulated for the therapeutic management of the intractable forms of Crohn's disease and ulcerative colitis, the two major forms of inflammatory bowel disease. These advances are based largely on new insights into the immune-inflammatory events occurring in the gut of these patients. Analysis of the types of immune response ongoing in the inflamed intestine has revealed that in Crohn's disease there is predominantly a T-helper cell type 1 response, with exaggerated production of interleukin (IL)-12 and interferon (IFN)-gamma, whereas in ulcerative colitis the lesion seems more of an antibody-mediated hypersensitivity reaction. Despite these differences, downstream inflammatory events are the same in both conditions. In both Crohn's disease and ulcerative colitis mucosa, IL-1gamma, IL-6, IL-8 and tumour necrosis factor (TNF)-alpha are produced in excess, and the production of free radicals accompanying the influx of nonspecific inflammatory cells into the mucosa is above the normal range. Strategies aimed at inhibiting T-cell responses are therefore more relevant in Crohn's disease, whereas, in theory at least, inhibition of downstream inflammatory processes should be therapeutic in both Crohn's disease and ulcerative colitis. This review seeks to summarize studies in which anticytokine antibodies, cytokines or cytokine-modifying agents have been used in the treatment of either Crohn's disease or ulcerative colitis.
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PMID:Manipulation of cytokines in the management of patients with inflammatory bowel disease. 1112 33

Cytokine-mediated impairment of viability and metabolic function of epithelial cells has been suggested as a possible early pathogenic event in the development of inflammatory bowel disease (IBD). It is currently unknown whether pro-inflammatory cytokines have a direct effect on human nontransformed colonic epithelial cells. We investigated the effects of TNFalpha, IFNgamma and IL-1beta on viability, short chain fatty acid (butyrate) oxidation and IL-8 secretion in human colonic epithelial cell cultures in vitro obtained from macroscopically normal mucosa from IBD patients and controls. Colonic crypts were isolated from endoscopical biopsies by ultra-short (10 min) EDTA/EGTA treatment, and exposed to TNFalpha, IFNgamma and IL-1beta for 24 hours. The combination of TNFalpha+IFNgamma induced a significant decrease in cell viability as judged by methyltetrazoleum (MTT) metabolism which decreased to median 68% of unexposed cultures (P < 0.01). This effect was more pronounced than that observed after addition of TNFalpha (median 88%) (P < 0.05), but not IFNgamma alone (median 78%), whereas IL-1beta had no significant effect. Cells from IBD patients were significantly less sensitive to TNFalpha + IFNgamma exposure (median 74%) compared to cells from controls (median 58 %) (P < 0.05). Butyrate oxidation, as measured by entrapment of 14CO2, was not inhibited in cells exposed to TNFalpha + IFNgamma, neither from controls (median 112%) nor from IBD patients (median 108%), suggesting a relative increase of this specific metabolic function in living cells in response to immunoinflammatory stress. IL-8 levels in cell supernatants were increased by TNFalpha + IFNgamma, supporting the role of the epithelium in signalling between luminal factors and mucosal immune cells. In conclusion, we report that TNFalpha and IFNgamma damage and influence human colonic epithelial cell function in vitro and that such mechanisms, if operative in vivo, also may be involved in the pathogenesis of IBD.
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PMID:Cultures of human colonic epithelial cells isolated from endoscopical biopsies from patients with inflammatory bowel disease. Effect of IFNgamma, TNFalpha and IL-1beta on viability, butyrate oxidation and IL-8 secretion. 1119 Dec 84

Matrix metalloproteinase-9 (MMP-9) may play an important role in the development of inflammatory bowel disease (IBD). However, the cellular source of MMP-9 in the inflamed mucosa of IBD remains unclear. Here we report that MMP-9 mRNA is expressed in CaCO-2 cells, an intestinal epithelial cell line, and that its expression is upregulated by inflammatory stimuli. Stimulation of CaCO-2 cells with interleukin-1beta (IL-1beta) or tumor necrosis factor-alpha (TNF-alpha) led to a dose-dependent increase in expression and secretion of MMP-9. In contrast, bacterial lipopolysaccharide (LPS) failed to induce expression or secretion of MMP-9, suggesting that an inflammatory reaction leading to cytokine release is a necessary step for the induction of MMP-9 release in intestinal epithelial cells. Additional studies show that induction of MMP-9 mRNA peaked at 16 h of IL-1beta stimulation, whereas expression of monocyte chemoattractant protein-1 (MCP-1) and IL-8 both peaked at 3 h of stimulation. Treatment of CaCO-2 cells with rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, significantly reduced secretion of MMP-9, indicating that agents that activate PPAR-gamma may have therapeutic use in patients with IBD.
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PMID:Production of matrix metalloproteinase-9 in CaCO-2 cells in response to inflammatory stimuli. 1124 73


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