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)

Interleukin (IL)-23 is a heterodimeric cytokine closely related to IL-12. Yet, despite a strong structural relationship that includes a shared p40 subunit, this does not translate into functional similarity. In fact, the opposite is true, in that these two cytokines appear to have profoundly different roles in regulating host immune responses. It is now clear that IL-23 has key roles in autoimmune destruction in experimental allergic encephalomyelitis, collagen-induced arthritis and inflammatory bowel disease. IL-23 drives the development of autoreactive IL-17-producing T cells and promotes chronic inflammation dominated by IL-17, IL-6, IL-8 and tumor necrosis factor as well as neutrophils and monocytes. It is unlikely that IL-23 and its downstream effects evolved just to cause autoimmunity, but its real benefit to the host and the lineage relationship between IL-17-producing cells and T helper 1 cells remain unclear. By comparing the pathophysiological function of IL-12 and IL-23 in the context of host defense and autoimmune inflammation, we are beginning to understand the novel IL-23-IL-17 immune pathway.
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PMID:Understanding the IL-23-IL-17 immune pathway. 1629 Feb 28

Initially used to treat rheumatoid arthritis, nonselective therapeutic leukocytapheresis was applied to the treatment of inflammatory bowel disease (IBD) as early as the 1980s. Since then, the process has been further refined and 2 blood perfusion systems using membrane filtration are presently employed in Japan and Europe for the selective removal of leukocytes in patients with IBD: Cellsorba is a column of polyethylenephtarate fibers that captures lymphocytes and granulocytes, and Adacolumn is a column of cellulose acetate beads that selectively adsorb granulocytes and monocytes. These systems overcome the limitations of centrifugation. Leukocytapheresis has been shown to exert an overall anti-inflammatory effect, as peripheral leukocytes demonstrated a diminished capacity to produce inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, IL-8, and IL-1beta. In addition, down-regulation in the expression of adhesion molecule L-selectin and a shift toward a more immature granulocyte phenotype were observed in the peripheral blood. The safety and beneficial therapeutic effect of leukocytapheresis in IBD are being investigated further.
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PMID:Developments in the apheresis procedure for the treatment of inflammatory bowel disease. 1637 5

In order to selectively block nuclear factor kappaB (NF-kappaB)-dependent signal transduction in angiogenic endothelial cells, we constructed an alphavbeta3 integrin specific adenovirus encoding dominant negative IkappaB (dnIkappaB) as a therapeutic gene. By virtue of RGD modification of the PEGylated virus, the specificity of the cell entry pathway of adenovirus shifted from coxsacki-adenovirus receptor dependent to alphavbeta3 integrin dependent entry. The therapeutic outcome of delivery of the transgene into endothelial cells was determined by analysis of cellular responsiveness to tumor necrosis factor (TNF)-alpha. Using real time reverse transcription PCR, mRNA levels of the cell adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1, the cytokines/growth factors IL-6, IL-8 and vascular endothelial growth factor (VEGF)-A, and the receptor tyrosine kinase Tie-2 were assessed. Furthermore, levels of ICAM-1 protein were determined by flow cytometric analysis. RGD-targeted adenovirus delivered the dnIkappaB via alphavbeta3 to become functionally expressed, leading to complete abolishment of TNF-alpha-induced up-regulation of E-selectin, ICAM-1, VCAM-1, IL-6, IL-8, VEGF-A and Tie-2. The approach of targeted delivery of dnIkappaB into endothelial cells presented here can be employed for diseases such as rheumatoid arthritis and inflammatory bowel disease where activation of NF-kappaB activity should be locally restored to basal levels in the endothelium.
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PMID:Functional inhibition of NF-kappaB signal transduction in alphavbeta3 integrin expressing endothelial cells by using RGD-PEG-modified adenovirus with a mutant IkappaB gene. 1680 39

Pathogenic mechanisms responsible for inflammatory bowel disease (IBD) are poorly understood. In an IBD animal model, the oral administration of polysaccharides such as dextran sulfate sodium (DSS) induces colitis, which exhibit several clinical and histological features for IBD. However, pathogenic factors in the development of colitis remain unclear. Therefore, we investigated possible mechanisms for DSS-induced colitis, and mainly focused on biological responses from an intestinal epithelial cell line, Caco-2. Cytotoxicity and cytokine release were measured using MTS assays and ELISA, respectively. The effect of DSS on the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers was also evaluated. Cell cycle progression was estimated using antibodies directed against p53 and cdc-2 proteins. The generation of reactive oxygen species (ROS) was measured using a DCFH-DA method. Pyridylamino-DSS (PA-DSS) was used as a fluorometric label in order to investigate fluorescence-microscopically the location of DSS in Caco-2 cells. DSS induced cytotoxicity on Caco-2 cells at 5%. DSS also induced strong TEER decrease at 3%. DSS induced the weak release of IL-8, IL-6, and TGF-beta1. Remarkably DSS arrested Caco-2 cell cycle and reduced the intracellular generation of ROS. Under fluorescence microscopy, PA-DSS entered cells and bound to the nucleus, indicating this binding of DSS may be involved in the cell cycle arrest of Caco-2 cells. The cell cycle arrest and reduced intracellular generation of ROS may be involved during initiation or throughout the early stages of DSS-induced colitis.
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PMID:In vitro effects of dextran sulfate sodium on a Caco-2 cell line and plausible mechanisms for dextran sulfate sodium-induced colitis. 1708 61

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

Infectious bursal disease virus (IBDV) is the causative agent of infectious bursal disease in chickens and causes a significant economic loss for the poultry industry. Little is understood about the mechanism involved in the host responses to IBDV infection. For better understanding the IBDV-host interaction, we measured steady-state levels of transcripts from 28 cellular genes of chicken embryo (CE) cell cultures infected with IBDV vaccine stain Bursine-2 during a 7-day infection course by use of the quantitative real-time RT-PCR SYBR green method. Of the genes tested, 21 genes (IRF-1, IFN 1-2 promoter, IFNAR-1, IRF-10, IFN-gamma, 2',5'-OAS, IAP-1, caspase 8, TRAIL-like, STAT-3, IL-6, IL-8, MIP-3 alpha, MHC-I, MHC-II, TVB, GLVR-1, OTF, IL-13R alpha, ST3GAL-VI and PGK) showed an increased expression. The remaining seven genes (IFNAR-2, IFN-alpha, NF-kappaB subunit p65, BLRcp38, DDX1, G6PDH and UB) showed a constant expression or only slight alteration. Apparently, the host genes involved in pro-inflammatory response and apoptosis, interferon-regulated proteins, and the cellular immune response were affected by IBDV infection, indicating involvement in the complex signaling pathways of host responses to the infection. This study thus contributes to the understanding of the pathogenesis of IBD and provides an insight into the virus-host interaction.
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PMID:Transcriptional profiles of chicken embryo cell cultures following infection with infectious bursal disease virus. 1714 81

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

Statins, HMG-CoA reductase inhibitors exert pleiotropic anti-inflammatory properties in vitro and in vivo, and are associated with the risk reduction of colorectal cancer. It remains unknown, however, whether statin is effective for the treatment of inflammatory bowel disease (IBD). Therefore, we investigated anti-inflammatory effects of simvastatin on intestinal epithelial cells (IEC) and on an experimental murine colitis model, and elucidated its molecular mechanisms. Simvastatin (50 micro M) significantly inhibited TNF-alpha-induced IL-8 gene expression in COLO 205 cells. Simvastatin (50 micro M) blocked TNF-alpha-induced NF-kappaB transcriptional activity, IkappaB phosphorylation/degradation and DNA binding activity of NF-kappaB. Administration of simvastatin significantly reduced the severity of dextran sulfate sodium (DSS)-induced murine colitis as assessed by body weight, colon length, DAI, and histology in a dose-dependent manner. These results suggest that simvastatin inhibits proinflammatory gene expression by blocking NF-kappaB signaling in IEC, and attenuates DSS-induced acute murine colitis. Simvastatin could be a potential agent for the treatment of IBD.
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PMID:Simvastatin inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis. 1717 92

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

Lipopolysaccharide (LPS) and inflammatory cytokines cause activation of sphingomyelinases (SMases) and subsequent hydrolysis of sphingomyelin (SM) to produce a lipid messenger ceramide. The use of SMase inhibitors may offer new therapies for the treatment of the LPS- and cytokines-related inflammatory bowel disease (IBD). We synthesized a series of difluoromethylene analogues of SM (SMAs). Here, we show that LPS efficiently increases the release of IL-8 from HT-29 intestinal epithelial cells by activating both neutral SMase and nuclear factor (NF)-kappaB in the cells. The addition of SMA-7 suppressed neutral SMase-catalyzed ceramide production, NF-kappaB activation, and IL-8 release from HT-29 cells caused by LPS. The results suggest that activation of neutral SMase is an underlying mechanism of LPS-induced release of IL-8 from the intestinal epithelial cells. Ceramide production following LPS-induced SM hydrolysis may trigger the activation of NF-kappaB in nuclei. Oral administration of SMA-7 (60 mg/kg) to mice with 2% dextran sulfate sodium (DSS) in their drinking water, for 21 consecutive days, reduced significantly the severity of colonic injury. This finding suggests a central role for SMase/ceramide signaling in the pathology of DSS-induced colitis in mice. The therapeutic effect of SMA-7 observed in mice may involve the suppression of IL-8 production from intestinal epithelial cells by LPS or other inflammatory cytokines.
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PMID:Inhibition of lipopolysaccharide-induced release of interleukin-8 from intestinal epithelial cells by SMA, a novel inhibitor of sphingomyelinase and its therapeutic effect on dextran sulphate sodium-induced colitis in mice. 1746 62


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