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)

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

Inflammatory bowel disease (IBD) is characterized by an exaggerated immune response that involves pro-inflammatory cytokines including IL-8. Production of these pro-inflammatory cytokines is triggered by pathogen-associated molecular patterns (PAMP). Butyrate, a product of bacterial fermentation of carbohydrates, has been reported to modulate inflammation in IBD, possibly by regulating production of pro-inflammatory cytokines. However, this effect of butyrate is controversial. In this study, we used Pam3CSK4 (Pam3CysSerLys4), the acylated NH2-terminus of the bacterial lipoprotein (a PAMP), to mimic in vivo infection of pathogens. Butyrate transiently down-regulated expression of IL-8 stimulated by Pam3CSK4. Treatment of cells with butyrate before Pam3CSK4, however, enhanced production of IL-8. Furthermore, butyrate induced expression of A20, a negative regulator of the nuclear factor-kappaB pathway. Over-expression of A20 inhibited Pam3CSK4-triggered IL-8 expression. Our data suggest that the inflammatory modulation of butyrate in IBD is mediated by A20 and a short pulse rather than continuous administration of butyrate may provide a protective effect on IBD.
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PMID:Butyrate regulates the expression of pathogen-triggered IL-8 in intestinal epithelia. 1780 11

Saccharomyces boulardii is gaining in popularity as a treatment for a variety of diarrheal diseases as well as inflammatory bowel disease. This study was designed to examine the effect of this yeast on infection by Shigella flexneri, a highly infectious and human host-adapted enteric pathogen. We investigated key interactions between the bacteria and host cells in the presence of the yeast in addition to a number of host responses including proinflammatory events and markers. Although the presence of the yeast during infection did not alter the number of bacteria that was able to attach or invade human colon cancer-derived T-84 cells, it did positively impact the tight junction protein zonula occluden-2 and significantly increase the barrier integrity of model epithelia. The yeast also decreased ERK, JNK, and NF-kappaB activation in response to S. flexneri, events likely responsible for the observed reductions in IL-8 secretion and the transepithelial migration of polymorphonuclear leukocytes across T-84 monolayers. These results, suggesting that the yeast allowed for a dampened inflammatory response, were confirmed in vivo utilizing a highly relevant model of human fetal colonic tissue transplanted into scid mice. Furthermore, a cell-free S. boulardii culture supernatant was also capable of reducing IL-8 secretion by infected T-84 cells. These data suggest that although the use of S. boulardii during infection with S. flexneri may alleviate symptoms associated with the inflammatory response of the host, it would not prevent infection.
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PMID:Saccharomyces boulardii interferes with Shigella pathogenesis by postinvasion signaling events. 1803 77

Angiogenesis is the growth of new blood vessels. In the two major forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, robust angiogenesis exists, and its blockade may have therapeutic potential, as shown in animal models of experimental intestinal inflammation. While abundant literature is available on the positive regulators of intestinal pathological angiogenesis, e.g. VEGF, b-FGF, IL-8, CD40 and CD40L, almost no data exist on negative regulators. Thrombospondin-1 is a negative regulator of angiogenesis, and it plays a new role in IBD-associated angiogenesis. In addition, recombinant thrombospondin-1 may inhibit pathological angiogenesis and may offer a new therapeutic approach to intestinal inflammation.
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PMID:Negative regulators of angiogenesis in inflammatory bowel disease: thrombospondin in the spotlight. 1833 36

Recently we identified galectin-3 (gal-3), which is secreted by colonic epithelial cells (CEC), to be a strong activator of colonic lamina propria fibroblasts (CLPF). Modulation of CLPF function may play a role during stricture and fistula formation in inflammatory bowel disease (IBD). Therefore, we investigated further the expression of gal-3 and effects on CLPF. The aim of this study is to perform a direct comparison of gal-3 between tissue from healthy controls and from patients with either Crohn's disease (CD) or ulcerative colitis (UC). CEC, CLPF and intestinal macrophages (IMAC) were isolated from control and IBD colonic tissue. Interleukin-8 secretion as a readout of CLPF activation was quantified by enzyme-linked immunosorbent assay. Gal-3 in cell cultures and tissue samples was evaluated by Western blot, immunofluorescence and immunohistochemistry. CLPF-migration was assayed in the 48-well modified Boyden chamber. Gal-3 expression was found in all segments of the colon. In the terminal ileum, less gal-3 was found compared with the colon. Immunohistochemistry and immunofluorescence revealed a homogenous distribution of gal-3 in CEC and IMAC of control mucosa and UC. However, significantly less gal-3 was found in IMAC from CD patients. In CD fistulae and stenoses, gal-3 expression was reduced significantly and barely detectable. In co-incubation studies lactose reduced significantly the CLPF-stimulatory potential of gal-3, indicating that the C-terminal domain of gal-3 is responsible for CLPF activation. Gal-3 stimulated CLPF migration in CLPF derived from fistulae. In conclusion, gal-3 expression is down-regulated in CD-fistulae and stenoses as well as in IMAC in CD patients. Gal-3 induces migration of CLPF derived from fistulae. Its role for stricture and fistula formation warrants further investigation.
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PMID:Regulation of galectin-3 function in mucosal fibroblasts: potential role in mucosal inflammation. 1833 93

Bromelain, a mixture of proteases derived from pineapple stem, has been reported to have therapeutic benefits in a variety of inflammatory diseases, including murine inflammatory bowel disease. The purpose of this work was to understand potential mechanisms for this anti-inflammatory activity. Exposure to bromelain in vitro has been shown to remove a number of cell surface molecules that are vital to leukocyte trafficking, including CD128a/CXCR1 and CD128b/CXCR2 that serve as receptors for the neutrophil chemoattractant IL-8 and its murine homologues. We hypothesized that specific proteolytic removal of CD128 molecules by bromelain would inhibit neutrophil migration to IL-8 and thus decrease acute responses to inflammatory stimuli. Using an in vitro chemotaxis assay, we demonstrated a 40% reduction in migration of bromelain- vs. sham-treated human neutrophils in response to rhIL-8. Migration to the bacterial peptide analog fMLP was unaffected, indicating that bromelain does not induce a global defect in leukocyte migration. In vivo bromelain treatment generated a 50-85% reduction in neutrophil migration in 3 different murine models of leukocyte migration into the inflamed peritoneal cavity. Intravital microscopy demonstrated that although in vivo bromelain treatment transiently decreased leukocyte rolling, its primary long-term effect was abrogation of firm adhesion of leukocytes to blood vessels at the site of inflammation. These changes in adhesion were correlated with rapid re-expression of the bromelain-sensitive CD62L/L-selectin molecules that mediate rolling following in vivo bromelain treatment and minimal re-expression of CD128 over the time period studied. Taken together, these studies demonstrate that bromelain can effectively decrease neutrophil migration to sites of acute inflammation and support the specific removal of the CD128 chemokine receptor as a potential mechanism of action.
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PMID:Bromelain treatment decreases neutrophil migration to sites of inflammation. 1848 69

Oxidative stress and the activation of nuclear factor (NF)-kappaB play crucial roles in the pathogenesis of inflammatory bowel disease (IBD). In the present study, we examined the effects of the ethanol extract of Platycarya strobilacea Sieb. stem (EPS) on TNF-alpha-induced monocyte adhesion to HT29 human colon epithelial cells, an initial step of colon inflammation. EPS contained high amount of polyphenols (0.241+/-0.017 mg of catechin equivalent/g of extract) and showed substantial DPPH radical scavenging activity. In addition, EPS significantly suppressed TNF-alpha-induced reactive oxygen species (ROS) increase. Moreover, TNF-alpha-induced monocyte adhesion to HT29 colon epithelial cells was significantly suppressed by EPS in a concentration-dependent manner. The reduced adhesion by EPS was correlated with suppressed expression of MCP-1 and IL-8, the major chemokines in IBD. EPS also prevented the TNF-alpha-induced nuclear translocation of NF-kappaB, one of the redox-sensitive transcription factors, in a concentration-dependent manner. Taken together, our results suggest that the anti-oxidant components of EPS prevent TNF-alpha-induced NF-kappaB activation, chemokine induction, and monocyte adhesion at the site of intestinal inflammation.
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PMID:Involvement of NF-kappaB in the inhibitory actions of Platycarya strobilacea on the TNF-alpha-induced monocyte adhesion to colon epithelial cells and chemokine expression. 1856 54

Melanin-concentrating hormone (MCH) is expressed primarily in the hypothalamus and has a positive impact on feeding behavior and energy balance. Although MCH is expressed in the gastrointestinal tract, its role in this system remains elusive. We demonstrate that, compared to wild type, mice genetically deficient in MCH had substantially reduced local inflammatory responses in a mouse model of experimental colitis induced by intracolonic administration of 2,4,6 trinitrobenzene sulfonic acid (TNBS). Likewise, mice receiving treatments with an anti-MCH antibody, either prophylactically or after the establishment of colitis, developed attenuated TNBS-associated colonic inflammation and survived longer. Consistent with a potential role of MCH in intestinal pathology, we detected increased colonic expression of MCH and its receptor in patients with inflammatory bowel disease. Moreover, we found that human colonic epithelial cells express functional MCH receptors, the activation of which induces IL-8 expression. Taken together, these results clearly implicate MCH in inflammatory processes in the intestine and perhaps elsewhere.
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PMID:Melanin-concentrating hormone as a mediator of intestinal inflammation. 1865 Mar 83

Apple procyanidins (ACT) is a natural biologically active compound extracted from apple. Our recent studies have shown that ACT ameliorates the symptoms of atopic dermatitis and inhibits food-allergen-induced oral sensitization. The aim of this study was to investigate the potential protective effect and mechanism of action of ACT in a murine model of inflammatory bowel disease. We investigated the preventive effects of ACT in experimental models of colitis induced by dextran sulfate sodium (DSS) or oxazolone. Oral administration of ACT before DSS treatment attenuated the DSS-induced mortality rate and decreased body weight loss. ACT also prevented the body weight loss associated with oxazolone-induced colitis. Next we examined the effect of ACT on intraepithelial lymphocytes (IEL), which is a major T cell population in the intestine. Oral administration of ACT increased the proportions of TCRgammadelta and TCRalphabeta-CD8alphaalpha T cells in IEL and suppressed interferon gamma synthesis in stimulated IEL. In addition, ACT inhibited phorbol 12-myristate 13-acetate-induced secretion of interleukin 8 (IL-8) in intestinal epithelial cells. The combined anti-inflammatory and immunomodulatory effects of ACT on intestinal epithelial cells and IEL suggest that it may be an effective oral preventive agent for inflammatory bowel diseases.
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PMID:Orally administered apple procyanidins protect against experimental inflammatory bowel disease in mice. 1882 49

The IL-23/IL-17 pathway plays an important role in chronic inflammatory diseases, including inflammatory bowel disease. In inflammatory bowel disease, intestinal epithelial cells are an important source of chemokines that recruit inflammatory cells. We examined the effect of IL-17 on chemokine expression of HT-29 colonic epithelial cells. IL-17 strongly repressed TNF-alpha-stimulated expression of CXCL10, CXCL11, and CCL5, but synergized with TNF-alpha for induction of CXCL8, CXCL1, and CCL20 mRNAs. For CXCL10, IL-17 strongly inhibited promoter activity but had no effect on mRNA stability. In contrast, for CXCL8, IL-17 slightly decreased promoter activity but stabilized its normally unstable mRNA, leading to a net increase in steady-state mRNA abundance. IL-17 synergized with TNF-alpha in transactivating the epidermal growth factor receptor (EGFR) and in activating ERK and p38 MAPK. The p38 and ERK pathway inhibitors SB203580 and U0126 reversed the repressive effect of IL-17 on CXCL10 mRNA abundance and promoter activity and also reversed the inductive effect of IL-17 on CXCL8 mRNA, indicating that MAPK signaling mediates both the transcriptional repression of CXCL10 and the stabilization of CXCL8 mRNA by IL-17. The EGFR kinase inhibitor AG1478 partially reversed the effects of IL-17 on CXCL8 and CXCL10 mRNA, demonstrating a role for EGFR in downstream IL-17 signaling. The overall results indicate a positive effect of IL-17 on chemokines that recruit neutrophils (CXCL8 and CXCL1), and Th17 cells (CCL20). In contrast, IL-17 represses expression of CXCL10, CXCL11, and CCR5, three chemokines that selectively recruit Th1 but not other effector T cells.
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PMID:Differential regulation of chemokines by IL-17 in colonic epithelial cells. 1894 Dec 44


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