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)

TH17 is a newly identified pathogenic memory CD4 T-cell lineage with potent agonist effects in some murine experimental autoimmunity models, however, its role in tumor immunology is still unclear. Clinical experience with interleukin (IL)-2 and ipilumumab [anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody], particularly in treating immunogenic malignancies such as melanoma and renal cell carcinoma (RCC), has suggested an association between a variety of autoimmune phenomena and tumor regression. To investigate this issue in patients with RCC, we isolated T-cell clones from peripheral blood that released IL-17 on stimulation with their autologous RCC tumor line. Clones were generated from 1 patient before any systemic treatment by in vitro stimulation with dendritic cells, autologous tumor, and IL-2 in the presence of anti-CTLA4 antibody. That patient subsequently received treatment with ipilimumab and showed both objective tumor regression and immune-mediated colitis. Limiting dilution cloning of his tumor-dendritic cell-stimulated T cells produced the 3G8D CD4+ clone, which secreted both IL-17 and interferon-gamma when cocultured with the autologous RCC line (transduced with class II transactivation molecule to induce major histocompatibility complex-class II expression). Broader analysis of its cytokine secretion profile showed large amounts of IL-8 when cocultured with RCC, but not when triggered with phorbol 12-myristate 13-acetate and ionomycin. This led to the discovery that IL-8 was being produced by the RCC cells in response to T-cell-derived IL-17. This effect of exogenous IL-17 on IL-8 release from tumor was seen in 5 of 8 RCCs, but not in other tumors tested. Preliminary data on the frequency of IL-17-secreting T cells in the lymphocytes infiltrating RCCs suggest that there may be a positive correlation between this frequency and IL-8 production by nonlymphoid cells as determined by quantitative reverse transcription-polymerase chain reaction. This report extends the known bidirectional interactions between immune cells and malignant cells in the tumor microenvironment that can shape and modulate the host immune response to cancer.
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PMID:IL-17 secreted by tumor reactive T cells induces IL-8 release by human renal cancer cells. 1923 9

Effects of dietary taurine on the experimental colitis induced by dextran sulfate sodium (DSS) were studied. C57BL/6 mice administrated taurine or placebo for 5 days were given 3% DSS to induce acute. The colitis was as-sessed using indices such as diarrhea/bleeding scores, colon length change, histological score and tissue myeloperoxidase (MPO) activity. Further, tissue mRNA levels of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2, were determined by real-time PCR. Taurine supplementation significantly attenuated the severity of diarrhea, colon shortening, histological score, MPO activity elevation and abnormal MIP-2 gene expression, indicating that taurine prevents DSS-induced colitis. Taurine also inhibited the TNF-alpha-induced secretion of IL-8 (a human homologue of MIP-2) from human intestinal epithelial Caco-2 cells. Inhibition of chemokine secretion from intestinal cells may be involved in the mechanisms underlying the cytoprotective function of taurine in the intestinal epithelium.
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PMID:Dietary taurine attenuates dextran sulfate sodium (DSS)-induced experimental colitis in mice. 1923 57

Ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis are defined as inflammatory bowel diseases (IBD). Those diseases involve disorders of numerous immunological mechanisms associated with cellular and humoral immune response. In CD cellular response is considered to be of crucial importance, and dominant cytokines include: tumor necrosis factor alpha (TNF-alpha), interferon gamma (INF-gamma) and interleukins 1beta (IL-1beta), IL-2, IL-6, IL-8, IL-12. In UC, increased expression of Th2 (responsible for humoral response) is observed. It is connected with increased production of interleukins: 4 (IL-4), IL-5, IL-6, IL-10 and TNF-alpha. Lack of balance between pro-inflammatory and anti-inflammatory cytokines is of vital importance in pathogenesis of IBD. Conventional therapy of CD and UC quite commonly fails to bring satisfactory results, therefore an interest in new therapeutic options, that is, biological therapy, gene therapy, hematopoietic stem cell transplantation, and leucapheresis, has aroused recently. Biological therapy is focused on different stages of the inflammatory process. The fundamentals of biological strategy involve neutralization of pro-inflammatory cytokines, use of anti-inflammatory cytokines and inhibition of neutrophil adhesion. Biological therapy is a promising option because it enables to withdraw corticosteroids and immunosuppressive agents or to reduce their dose. Moreover, it shortens the hospital stay, allows to avoid surgical procedures, extends the remission period and improves patients' quality of life. Currently, 2 agents, infliximab and adalimumab, are registered for the biological therapy of CD in Poland.
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PMID:Biological therapy of inflammatory bowel disease. 1934 Nov 84

Interleukin 2 (IL-2)- and IL-10-knockout mice develop spontaneous colitis under conventional but not germ-free conditions, suggesting that commensal bacteria play an important role in the pathogenesis of colitis. However, interactions between commensal bacteria and colonic epithelial cells have not been fully investigated. We therefore assessed the ability of various commensal bacteria and probiotics to adhere to and invade colonic epithelial cells. Effects of the bacteria on production of proinflammatory cytokines were also measured. Commensal bacteria, including mucosal organisms isolated from ulcerative colitis (UC) patients, such as Fusobacterium varium, reported as a possible pathogen in UC, Bacteroides vulgatus, Escherichia coli and Clostridium clostridioforme, as well as their type strains and probiotics, were assessed for their ability to adhere to and invade colonic epithelial cells using two cell lines, SW-480 and HT-29. Our experiments employed co-incubation, a combination of scanning and transmission electron microscopy and recovery of bacteria from infected-cell lysates. F. varium and several other commensal bacteria, but not probiotics, adhered to colonic epithelial cells and invaded their cytoplasm. ELISA and real-time PCR revealed that the host cells, particularly those invaded by F. varium, showed significant increases in IL-8 and TNF-alpha concentrations in supernatants, with elevation of IL-8, TNF-alpha, MCP-1 and IL-6 mRNAs. Furthermore, IL-8 and TNF-alpha expression and nuclear phosphorylated NF-kappaB p65 expression could be immunohistochemically confirmed in inflamed epithelium with cryptitis or crypt abscess in UC patients. Certain commensal bacteria can invade colonic epithelial cells, activating early intracellular signalling systems to trigger host inflammatory reactions.
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PMID:Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis. 1936 13

Conventional therapies for the treatment of inflammatory bowel disease (IBD) have demonstrated limited efficacy and potential toxicity; therefore, there is a need for novel therapies that can safely and effectively treat IBD. Recent evidence has indicated that amino acids may play a role in maintaining gut health. L-tryptophan has been shown to reduce oxidative stress and improve neurological states. The objective of this study was to assess the therapeutic effects of L-tryptophan in a porcine model of dextran sodium sulfate (DSS)-induced colitis. DSS was administered to piglets via intragastric catheter for 5 days followed by tryptophan administration at 80% of the daily recommended intake. The severity of colitis was assessed macroscopically and histopathologically, and intestinal permeability was monitored in vivo by D-mannitol analysis. The effect of tryptophan on the local expression of key mediators of inflammation and IBD pathogenesis was examined at the protein and gene expression levels. Supplementation with tryptophan ameliorated clinical symptoms and improved weight gain to feed intake conversion ratios. Histological scores and measurements were also improved, and gut permeability was notably reduced in tryptophan-supplemented animals. Moreover, tryptophan reduced the expression of the pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-6, interferon (IFN)-gamma, IL-12p40, IL-1beta and IL-17, as well as IL-8 and intracellular adhesion molecule-1, and resulted in increased expression of apoptosis initiators caspase-8 and Bax. These results demonstrate that L-tryptophan supplementation can reduce inflammation and enhance the rate of recovery in DSS-induced colitis and may be an effective immunomodulating agent for the treatment of IBD.
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PMID:l-Tryptophan exhibits therapeutic function in a porcine model of dextran sodium sulfate (DSS)-induced colitis. 1942 34

The effects of lactobacilli on impaired intestinal barrier function and paracellular permeability were evaluated in human epithelial Caco-2 cells treated with tumor necrosis factor-alpha and in mice with colitis induced by dextran sodium sulfate (DSS). Filter-grown Caco-2 monolayers were used as the intestinal epithelial model. Among the 4 lactobacilli studied, Lactobacillus rhamnosus OLL2838 most effectively suppressed barrier impairment and increased IL-8 secretion induced by tumor necrosis factor-alpha in Caco-2 cells; however, the conditioned medium from OLL2838 did not show any effect on barrier functions. The in vivo effects of OLL2838 on intestinal epithelial barrier function and colonic inflammation were assessed in DSS-induced colitis of BALB/c mice. Oral treatment with both live and heat-killed OLL2838 suppressed weight loss and recovered colon length. Additionally, barrier function was restored by the administration of live and heat-killed OLL2838 to the DSS-treated animals, which conferred protection against the increase in mucosal permeability associated with DSS-induced colitis. This may at least partially be because of the increased expression of zonula occludens-1 (4.8-fold) and myosin light-chain kinase (3.1-fold) in intestinal epithelial cells isolated from mice of the heat-killed OLL2838 group. Therefore, L. rhamnosus OLL2838 would be useful in the treatment of gastrointestinal diseases such as inflammatory bowel disease.
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PMID:Lactobacillus rhamnosus alleviates intestinal barrier dysfunction in part by increasing expression of zonula occludens-1 and myosin light-chain kinase in vivo. 1944 72

Infection with the enteric pathogen enterohemorrhagic Escherichia coli (EHEC) causes a variety of symptoms ranging from nonbloody diarrhea to more severe sequelae including hemorrhagic colitis, altered sensorium and seizures, and even life-threatening complications, such as hemolytic uremic syndrome and thrombotic thrombocytopenic purpura. The more severe consequences of EHEC infection are attributable to the production of Shiga toxin (Stx) and its subsequent effects on the vasculature, which expresses high levels of the Stx receptor, Gb3. Interestingly, the intestinal epithelium does not express Gb3. Despite the lack of Gb3 receptor expression, intestinal epithelial cells translocate Stx. The effect of Stx on intestinal epithelial cells is controversial with some studies demonstrating induction of inflammation and others not. This may be difficult to resolve because EHEC expresses both proinflammatory molecules, such as flagellin, and factor(s) that dampen the inflammatory response of epithelial cells. The goal of our study was to define the effect of Stx on the inflammatory response of intestinal epithelial cells and to determine whether infection by EHEC modulates this response. Here we show that Stx is a potent inducer of the inflammatory response in intestinal epithelial cells and confirm that EHEC attenuates the induction of IL-8 by host-derived proinflammatory cytokines. More importantly, however, we show that infection with EHEC attenuates the inflammatory response by intestinal epithelial cells to its own toxin. We speculate that the ability of EHEC to dampen epithelial cell inflammatory responses to Stx and cytokines facilitates intestinal colonization.
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PMID:Enterohemorrhagic Escherichia coli suppresses inflammatory response to cytokines and its own toxin. 1955 13

The polyphenols in fruits and vegetables may be partly responsible for the health-promoting effects attributed to fruit and vegetable intake. Although their properties have been relatively well studied, the activity of their metabolites, produced after ingestion, has been poorly investigated. Thus, the aim of this work was to study the potential anti-inflammatory effect of 18 polyphenol metabolites, derived from colon microbiota. They were screened by measuring prostaglandin E(2) (PGE(2)) production by CCD-18 colon fibroblast cells stimulated with IL-1beta. Metabolites that inhibited more than 50% PGE(2) production were hydrocaffeic (HCAF), dihydroxyphenyl acetic (dOHPA), and hydroferulic acid (HFER), that subsequently were tested with the writhing and paw pressure test in rodents where all three compounds showed an anti-inflammatory effect. The effect of HCAF administered orally (50 mg/kg) was also tested in the dextran sodium sulfate (DSS)-induced colitis model. Weight loss and fecal water content were more pronounced in DSS rats than in DSS-HCAF treated rats. HCAF treatment diminished the expression of the cytokines IL-1beta, IL-8, and TNF-alpha, reduced malonyldialdehyde (MDA) levels and oxidative DNA damage (measured as 8-oxo-2'-deoxyguanosine levels) in distal colon mucosa. These results indicate that HCAF, dOHPA, and HFER have anti-inflammatory activity in vitro and in vivo.
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PMID:Polyphenol metabolites from colonic microbiota exert anti-inflammatory activity on different inflammation models. 1955 20

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is characterized by chronic mucosal injury and the infiltration of inflammatory cells. Tumor suppressor FOXO3 regulates gene expression and its translocation to the cytosol leads to the abrogation of its transcriptional function. We have previously shown that bacterial infection regulates FOXO3 in intestinal epithelial cells and increases cytokine levels. As TNFalpha is a major contributor in intestinal inflammation, the aim of this study was to assess its effect on FOXO3 and FOXO3's contribution to intestinal inflammation in vitro and in vivo. TNFalpha induces the translocation of nuclear FOXO3 into the cytosol where it undergoes proteasomal degradation in human intestinal HT-29 cells. Proximally, the PI3K and IKK pathways mediate TNFalpha-induced FOXO3 phosphorylation. In FOXO3-silenced HT-29 cells, TNFalpha-induced IL-8 expression is increased approximately 83%. In vivo, Foxo3 is present in the nuclei and cytosol of colonic crypt epithelia. In DSS-induced colonic inflammation, Foxo3's nuclear localization is lost and it is only found in the cytosol. Consistent with a role for Foxo3 in colitis, Foxo3-deficient mice treated with DSS developed more severe colonic inflammation with an increased number of intraepithelial lymphocytes and PMNs infiltrated in the epithelia, than wild-type mice. In summary, TNFalpha inactivates FOXO3 in intestinal epithelia through the PI3K and IKK pathways and FOXO3 inactivation leads to the upregulation of IL-8 in vitro; in vivo Foxo3 is in the cytosol of inflamed colonic epithelia and Foxo3 deficiency leads to severe intestinal inflammation.
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PMID:Tumor suppressor FOXO3 participates in the regulation of intestinal inflammation. 1963 95

Probiotics have been used to treat human gastrointestinal inflammations including inflammatory bowel disease (IBD). However, the exact mechanisms by which probiotics act to protect against intestinal inflammation have yet to be fully elucidated. The aim of this study was to evaluate anti-inflammatory effects of Lactococcus lactis subsp. cremoris FC using in vivo and in vitro inflammation models. Colitis was induced in C57BL/6 mice by administration of 3% dextran sulfate sodium to drinking water. In the cellular level assessment, a gut inflammation model with the co-culture system consisting Caco-2 cells and RAW264.7 cells stimulated by LPS was used. Administration of L. lactis subsp. cremoris FC significantly ameliorated shortening of colon length and histological score of the colon in DSS-induce colitis mice. In addition, the treatment of L. lactis subsp. cremoris FC improved the aberrant mRNA expression in inflamed tissue near to control level through notable suppression of TNF-alpha (P<0.05), IFN-gamma (P<0.05), IL-6, iNOS, and MIP-2 mRNA expression. In addition, in a gut inflammation model, treatment with L. lactis subsp. cremoris FC resulted in significant down-regulation of IL-8 mRNA expression in Caco-2 cells and inhibition of NF-kappaB nuclear translocation in RAW264.7 cells. Our findings indicate that administration of L. lactis subsp. cremoris FC improves negative effects of DSS-induced colitis in mice through the inhibition of inflammatory cell infiltration.
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PMID:Lactococcus lactis subsp. cremoris FC alleviates symptoms of colitis induced by dextran sulfate sodium in mice. 1973 97


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