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)

Triggering receptor expressed on myeloid cells-1 (TREM-1) potently amplifies acute inflammatory responses by enhancing degranulation and secretion of proinflammatory mediators. Here we demonstrate that TREM-1 is also crucially involved in chronic inflammatory bowel diseases (IBD). Myeloid cells of the normal intestine generally lack TREM-1 expression. In experimental mouse models of colitis and in patients with IBD, however, TREM-1 expression in the intestine was upregulated and correlated with disease activity. TREM-1 significantly enhanced the secretion of relevant proinflammatory mediators in intestinal macrophages from IBD patients. Blocking TREM-1 by the administration of an antagonistic peptide substantially attenuated clinical course and histopathological alterations in experimental mouse models of colitis. This effect was also seen when the antagonistic peptide was administered only after the first appearance of clinical signs of colitis. Hence, TREM-1-mediated amplification of inflammation contributes not only to the exacerbation of acute inflammatory disorders but also to the perpetuation of chronic inflammatory disorders. Furthermore, interfering with TREM-1 engagement leads to the simultaneous reduction of production and secretion of a variety of pro-inflammatory mediators such as TNF, IL-6, IL-8 (CXCL8), MCP-1 (CCL2), and IL-1beta. Therefore, TREM-1 may also represent an attractive target for the treatment of chronic inflammatory disorders.
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PMID:TREM-1--expressing intestinal macrophages crucially amplify chronic inflammation in experimental colitis and inflammatory bowel diseases. 1785 46

Carrageenans are highly sulfated polysaccharides that are widely used as food additives due to their ability to improve food texture. They are also widely recognized for their ability to induce inflammation in animal models of colitis. Recently, we reported that carrageenan (CGN) activated a pathway of innate immunity in human colonic epithelial cells mediated by Bcl10 (B-cell CLL/lymphoma 10). However, increases in phospho-IkappaBalpha and Interleukin-8 (IL-8) were not completely inhibited by silencing Bcl10, suggesting that CGN also influenced another mechanism, or mechanisms, of inflammation. In this report, we demonstrate that CGN increases production of reactive oxygen species (ROS) in human colonic epithelial cells. The combination of ROS quenching by the free radical scavenger Tempol and of Bcl10 silencing by siRNA completely inhibited the CGN-induced increases in nuclear NFkappaB (p65), phospho-IkappaBalpha, and secretion of IL-8. The CGN-induced increase in ROS was associated with declines in phosphorylation of MAPK 12 (p38gamma), MAPK 13 (p38delta), and heat-shock protein (Hsp) 27. The CGN-induced decline in phospho-Hsp27 was reversed by co-administration of Tempol (100 nM), but unaffected by silencing Bcl10. Since Hsp27 phosphorylation is inversely associated with phosphorylation of the IkappaBalpha kinase (IKK) signalosome, CGN exposure appears to affect the IKK signalosome by both the catalytic component, mediated by ROS-phospho-Hsp27, and the regulatory component, mediated by Bcl10 interaction with IKKgamma (Nemo). Hence, the CGN-activated inflammatory cascades related to innate immunity and to generation of ROS may be integrated at the level of the IKK signalosome.
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PMID:Carrageenan-induced NFkappaB activation depends on distinct pathways mediated by reactive oxygen species and Hsp27 or by Bcl10. 1845 17

Various therapies are used for inflammatory bowel diseases (IBD), though none seem to be extremely effective. AP-1 is a major transcription factor that upregulates genes involved in immune and proinflammatory responses. We investigated decoy oligodeoxynucleotide (ODN) targeting AP-1 to prevent dextran sulfate sodium (DSS)-induced colitis in mice. Functional efficacies of synthetic decoy and scrambled ODNs were evaluated in vitro by a reporter gene luciferase assay and measuring flagellin-induced IL-8 expression by HCT-15 cells transfected with ODNs. Experimental colitis was induced in mice with a 2.5% DSS solution in drinking water for 7 days, and decoy or scrambled ODNs were intraperitoneally injected from days 2 to 5. Colitis was assessed by weight loss, colon length, histopathology, and detection of myeloperoxidase (MPO), IL-1beta, and TNF-alpha in colon tissue. Therapeutic effects of AP-1 and NF-kappaB decoy ODNs were compared. Transfection of AP-1 decoy ODN inhibited AP-1 transcriptional activity in reporter assays and flagellin-induced IL-8 production in vitro. In mice, AP-1 decoy ODN, but not scrambled ODN, significantly inhibited weight loss, colon shortening, and histological inflammation induced by DSS. Further, AP-1 decoy ODN decreased MPO, IL-1beta, and TNF-alpha in colonic tissue of mice with DSS-induced colitis. The AP-1 decoy therapeutic effect was comparable to that of NF-kappaB decoy ODN, which also significantly decreased intestinal inflammation. Double-strand decoy ODN targeting AP-1 effectively attenuated intestinal inflammation associated with experimental colitis in mice, indicating the potential of targeting proinflammatory transcription factors in new therapies for IBD.
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PMID:Decoy oligodeoxynucleotide targeting activator protein-1 (AP-1) attenuates intestinal inflammation in murine experimental colitis. 1845 70

Reactive oxygen species (ROS) induce chemokines responsible for the recruitment of inflammatory cells to sites of injury or infection. Here we show that the plasma membrane Ca(2+)-permeable channel TRPM2 controls ROS-induced chemokine production in monocytes. In human U937 monocytes, hydrogen peroxide (H(2)O(2)) evokes Ca(2+) influx through TRPM2 to activate Ca(2+)-dependent tyrosine kinase Pyk2 and amplify Erk signaling via Ras GTPase. This elicits nuclear translocation of nuclear factor-kappaB essential for the production of the chemokine interleukin-8 (CXCL8). In monocytes from Trpm2-deficient mice, H(2)O(2)-induced Ca(2+) influx and production of the macrophage inflammatory protein-2 (CXCL2), the mouse CXCL8 functional homolog, were impaired. In the dextran sulfate sodium-induced colitis inflammation model, CXCL2 expression, neutrophil infiltration and ulceration were attenuated by Trpm2 disruption. Thus, TRPM2 Ca(2+) influx controls the ROS-induced signaling cascade responsible for chemokine production, which aggravates inflammation. We propose functional inhibition of TRPM2 channels as a new therapeutic strategy for treating inflammatory diseases.
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PMID:TRPM2-mediated Ca2+influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. 1854 50

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

Increased interleukin (IL)-8 plays an important role not only in activation and recruitment of neutrophils but also in inducing exaggerated angiogenesis at the inflamed site. In the present study, we investigated the fact that clotrimazole (CLT) inhibits intestinal inflammation, and the inhibitory action is mediated through suppression of IL-8 expression. In the trinitrobenzene sulfonic acid (TNBS)-induced rat colitis model, CLT dose-dependently protected from the TNBS-induced weight loss, colon ulceration, and myeloperoxidase activity increase. In the lesion site, CLT also suppressed the TNBS-induced angiogenesis, IL-8 expression, and nuclear factor (NF)-kappaB activation. In a cellular model of colitis using tumor necrosis factor (TNF)-alpha-stimulated HT29 colon epithelial cells, treatment with CLT significantly suppressed TNF-alpha-mediated IL-8 induction and NF-kappaB transcriptional activity revealed by a luciferase reporter gene assay. Furthermore, cotreatment with CLT and pyrrolidine dithiocarbamate, a NF-kappaB inhibitor, synergistically reduced the NF-kappaB transcriptional activity as well as IL-8 expression. In an in vitro angiogenesis assay, CLT suppressed IL-8-induced proliferation, tube formation, and invasion of human umbilical vein endothelial cells. The in vivo angiogenesis assay using chick chorioallantoic membrane also showed that CLT significantly inhibited the IL-8-induced formation of new blood vessels. Taken together, these results suggest that CLT may prevent the progression of intestinal inflammation by not only down-regulating IL-8 expression but also inhibiting the action of IL-8 in both colon epithelial and vascular endothelial cells during pathogenesis of intestinal inflammation.
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PMID:Clotrimazole ameliorates intestinal inflammation and abnormal angiogenesis by inhibiting interleukin-8 expression through a nuclear factor-kappaB-dependent manner. 1872 40

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

A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-kappaB activity, F. prausnitzii had no effect on IL-1beta-induced NF-kappaB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-gamma production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment.
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PMID:Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. 2355 27

Recently, the role of serine proteinases in the pathogenesis of inflammation and autoimmune diseases via interaction with the proteinase-activated receptor (PAR) has attracted attention. Activation of PAR has a pro-inflammatory effect through the overproduction of inflammatory cytokines such as interleukin (IL)-6 and IL-8. PAR(2) activation in human esophageal epithelial cells by trypsin induces NFkappaB- and AP-1-dependent IL-8 production in association with activation of p38 MAPK and ERK1/2, suggesting that esophageal inflammation may be induced by PAR(2) activation via reflux of trypsin. It has been also proposed that Helicobacter pylori (H. pylori) induces PAR expression in the gastric epithelial cells and H. pylori-derived serine proteinase promotes IL-8 production via PAR in the epithelial cells. In addition, an increase of PAR-dependent IL-8 production has been observed in H. pylori-infected human gastric mucosa, suggesting an important role for PAR(2) in the modulation of gastric inflammation associated with H. pylori. Recent studies have strongly indicated that tryptase and PAR are implicated in the pathogenesis of inflammatory bowel disease and experimental colitis. We demonstrated that anti-tryptase therapy may become a new therapeutic strategy in human ulcerative colitis. Thus, the role of PAR in the gastrointestinal tract has been gradually clarified, but further investigations are needed because the receptor has a variety of functions.
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PMID:Basic and translational research on proteinase-activated receptors: implication of proteinase/proteinase-activated receptor in gastrointestinal inflammation. 1909 87

Inflammatory bowel disease (IBD) is a chronic and recurring inflammation of the gastrointestinal tract, associated with a dysregulation of the mucosal immune system. There is an increasing prevalence of IBD; however, current pharmaceutical treatments are only moderately effective and have been associated with potential long-term toxicity. Lysozyme, a well-known antimicrobial protein found in large quantities in hen egg white, is a promising alternative for the treatment of IBD. A porcine model of dextran sodium sulfate (DSS)-induced colitis was used to examine the effect of hen egg lysozyme (HEL) supplementation on intestinal inflammation. Treatment with DSS resulted in weight loss, severe mucosal and submucosal inflammation, colonic crypt distortion, muscle wall thickening, down-regulation of mucin gene expression, and increased gastric permeability, but these symptoms were attenuated following supplementation with HEL and restored to basal levels observed in untreated control animals. Treatment with HEL also significantly reduced the local expression of pro-inflammatory cytokines TNF-alpha, IL-6, IFN-gamma, IL-8, and IL-17 while increasing the expression of the anti-inflammatory mediators IL-4 and TGF-beta, indicating that HEL may function as a potent anti-inflammatory and immunomodulator. Furthermore, the concomitant increases in TGF-beta and Foxp3 levels suggest that HEL may aid in restoring gut homeostasis by activating regulatory T cells, which are important in the regulation of the mucosal immune system. These results suggest that HEL is a promising novel therapeutic for the treatment of IBD.
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PMID:Hen egg lysozyme attenuates inflammation and modulates local gene expression in a porcine model of dextran sodium sulfate (DSS)-induced colitis. 1923 58


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