Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epithelial ovarian cancer (EOC) represents the most frequent cause of death in the United States from a cancer involving the female genital tract. Contributing to the overall poor outcome in EOC patients, are the metastases to the peritoneum and stroma that are common in this cancer. In one study, cDNA microarray analysis was performed on fresh tissue to profile gene expression in patients with EOC. This study showed a number of genes with significantly altered expression in the pelvic peritoneum and stroma, and in the vicinity of EOC implants. These genes included those encoding coagulation factors and regulatory proteins in the coagulation cascade and genes encoding proteins associated with inflammatory responses. In addition to promoting the formation of blood clots, coagulation factors exhibit many other biologic functions as well as tumorigenic functions, the later including tumor cell proliferation, angiogenesis, invasion, and metastasis. Coagulation pathway proteins involved in tumorigenesis consist of factor II (thrombin), thrombin receptor (protease-activated receptors), factor III (tissue factor), factor VII, factor X and factor I (fibrinogen), and fibrin and factor XIII. In a recent study we conducted, we found that factor XII, factor XI, and several coagulation regulatory proteins, including heparin cofactor-II and epithelial protein C receptor (EPCR), were also upregulated in the peritoneum of EOC. In this review, we summarize evidence in support of a role for these factors in promoting tumor cell progression and the formation of ascites. We also discuss the different roles of coagulation factor pathways in the tumor and peritumoral microenvironments as they relate to angiogenesis, proliferation, invasion, and metastasis. Since inflammatory responses are another characteristic of the peritoneum in EOC, we also discuss the linkage between the coagulation cascade and the cytokines/chemokines involved in inflammation. Interleukin-8, which is considered an important chemokine associated with tumor progression, appears to be a linkage point for coagulation and inflammation in malignancy. Lastly, we review findings regarding the inflammatory process yielded by certain clinical trials of agents that target members of the coagulation cascade in the treatment of cancer. Current data suggest that disrupting certain elements of the coagulation and inflammation processes in the tumor microenvironment could be a new biologic approach to cancer therapeutics.
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PMID:Ovarian cancer, the coagulation pathway, and inflammation. 1596 48

We have previously reported that protease-activated receptor 1 (PAR1 or thrombin receptor) is over-expressed in metastatic prostate cancer cell lines compared to prostate epithelial cells. In this study, we examined 1,074 prostate biopsies by tissue microarray analysis and demonstrated that PAR1 expression is significantly increased in prostate cancer compared to normal prostate epithelial cells and benign prostatic hyperplasia. We hypothesized that PAR1 activation contributed to prostate cancer cell progression. We demonstrated that stimulation of PAR1 by thrombin or thrombin receptor activating peptide (TRAP6), in androgen-independent DU145 and PC-3 cells resulted in increased DNA binding activity of the NFkappaB p65 subunit. IL-6 and IL-8 levels were also elevated in conditioned media by at least two-fold within 4-6 h of PAR1 activation. This induction of cytokine production was abrogated by pretreatment of cells with the NFkappaB inhibitor caffeic acid phorbol ester. The p38 and ERK1/2 MAPK signaling cascades were also activated by PAR1 stimulation, whereas the SAPK/JNK pathway was unaffected. Inhibition of p38 and ERK1/2 by SB-203589 and PD-098059, respectively, did not abrogate NFkappaB activity, suggesting an independent induction of NFkappaB by PAR1 stimulation. Furthermore, TUNEL assay showed that activation of PAR1 attenuated docetaxel induced apoptosis through the upregulation of the Bcl-2 family protein Bcl-xL. Akt activation was not observed, suggesting that drug resistance induced by PAR1 was independent of PI3K signaling pathway. Because thrombin and PAR1 are over-expressed in prostate cancer patients, targeting the inhibition of their interaction may attenuate NFkappaB signaling transduction resulting in decreased drug resistance and subsequent survival of prostate cancer cells.
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PMID:PAR1-mediated NFkappaB activation promotes survival of prostate cancer cells through a Bcl-xL-dependent mechanism. 1605 12

Prior genomic and genetic studies identified pre-B-cell colony-enhancing factor (PBEF) as a novel candidate gene and biomarker in acute lung injury (ALI). As increased vascular permeability is a cardinal feature of ALI, we assessed the role of PBEF in in vitro vascular barrier regulation using confluent human pulmonary artery endothelial cell (HPAEC) monolayers. Reductions in PBEF protein expression (>70%) by siRNA significantly attenuated EC barrier dysfunction induced by the potent edemagenic agent, thrombin, reflected by reductions in transendothelial electric resistance (TER, approximately 60% reduction). Furthermore, PBEF siRNA blunted thrombin-mediated increases in Ca(2+) entry, polymerized actin formation, and myosin light chain phosphorylation, events critical to the thrombin-mediated permeability response. Finally, PBEF siRNA also significantly inhibited thrombin-stimulated increase of IL-8 secretion in HPAEC, a chemokine known to induce actin fiber formation and intercellular gap formation of endothelial cells. Taken together, these studies demonstrate that PBEF may be required for complete expression of the thrombin-induced inflammatory response and reveal potentially novel role for PBEF in the regulation of EC Ca(2+)-dependent cytoskeletal rearrangement and endothelial barrier dysfunction. Ongoing studies will continue to address the molecular mechanisms by which PBEF contributes to ALI susceptibility.
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PMID:Pre-B-cell-colony-enhancing factor is critically involved in thrombin-induced lung endothelial cell barrier dysregulation. 1618 81

Factor VIIa/tissue factor (FVIIa/TF) interaction has been reported to induce intracellular signalling in cells constitutively expressing TF, independently of downstream activation of the coagulation cascade. It is unknown, however, whether binding of FVII to its cofactor TF alters the gene expression profile in cells which inducible express TF under inflammatory conditions. To address this issue, gene expression patterns in cultured LPS-stimulated monocyte-derived macrophages with or without exposure to FVIIa were compared by cDNA macro-array analysis. Of the 1176 genes examined on the array, a small set of six genes (IL-6, IL-8,TNF-a, GRO-beta alpha-thymosin, cathepsin H) were consistently up-regulated and one gene suppressed (alpha-antitrypsin) in response to FVIIa in activated monocyte-derived macrophages. Among the seven genes identified by array analysis, five genes were finally confirmed by real-time RT-PCR. Interestingly, all of these genes differentially regulated in response to FVIIa (GRO-beta, IL-6, IL-8, TNF-alpha and alpha-antitrypsin) are critical in inflammation. The changes in gene expression were reflected by corresponding changes in the protein concentrations of IL-6 and IL-8 as demonstrated by ELISA. Active site-inhibited FVIIa had no effect on gene expression indicating that FVIIa-induced gene alteration is dependent on the proteolytic activity of FVIIa. The FVIIa-induced alterations in gene expression were found to be TF-dependent but independent of downstream coagulation proteins like thrombin and FXa. In summary, this study demonstrates that binding of FVIIa to its cofactor TF enhances restricted pro-inflammatory genes in activated monocyte-derived macrophages. By up-regulation of chemokines critical for leukocyte recruitment, FVIIa/TF interaction on activated monocyte-derived macrophages could be relevant to prepare monocytes/macrophages for extravasation and may represent a novel amplification loop of leukocyte recruitment.
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PMID:Differential gene expression in activated monocyte-derived macrophages following binding of factor VIIa to tissue factor. 1636 46

In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1beta, IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology.
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PMID:Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. 1641 Jul 50

Proteinase-activated receptors (PARs) are a novel family of G-protein-coupled receptors. PAR2 has been implicated in inflammatory airways disease. Although fibroblasts are pathologically important in the airways, the proinflammatory role of PAR2 in these cells remains unknown. We assessed PAR expression and functionality in human primary bronchial fibroblasts (HPBFs) before assessing PAR2-mediated HPBF proliferation, cytokine production, and adhesion molecule expression. RT-PCR and flow cytometry demonstrated that HPBFs express hPAR1, hPAR2, and hPAR3, but not hPAR4. Intracellular calcium signaling in HPBFs in response to PAR agonists showed that only hPAR1 and hPAR2 were functional receptors. We used the MTT assay to assess HPBF proliferation. Of the PAR2 agonist proteinases or selective PAR2-activating peptides (PAR2-APs) tested, none stimulated HPBF proliferation, whereas thrombin was a HPBF growth factor. mRNA for IL-8 and granulocyte colony-stimulating factor (G-CSF) was upregulated after addition of SLIGKV-NH2 when assessed by RT-PCR. No significant increase in G-CSF or IL-8 protein was detected. Trypsin stimulated IL-8 and G-CSF release from HPBF in a time- and dose-dependent manner. Leupeptin and soya trypsin inhibitor abrogated trypsin-stimulated cytokine release, indicating a requirement for trypsin's proteolytic activity. Trypsin and SLIGKV-NH2 stimulated an increase in VCAM-1 expression at 12 h after treatment, which declined thereafter. PAR2-driven upregulation of VCAM-1 cell surface expression and the release of IL-8 and G-CSF from bronchial fibroblasts may be important in promoting neutrophilic airways inflammation.
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PMID:Proteinase-activated receptor2 agonists upregulate granulocyte colony-stimulating factor, IL-8, and VCAM-1 expression in human bronchial fibroblasts. 1649 82

We investigated the effects of antithrombin on coagulation, fibrinolysis, and production of cytokines and adhesion molecules in abdominal aortic aneurysm repair surgery. Sixteen patients for Y-shaped graft replacement of abdominal aortic aneurysm were divided into an antithrombin group and a control group. In the antithrombin group, 3000 U antithrombin was infused over 30 min before heparin administration and 24 h later. White blood cell counts, platelet counts, prothrombin time ratio, and serum concentrations of antithrombin, polymorphonuclear leukocyte elastase, interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha, and adhesion molecules, and variables of coagulation and fibrinolysis were measured before surgery, at the end of surgery, and 1 and 2 days after surgery. The antithrombin concentration decreased in the control group, whereas it increased in the antithrombin group with significant differences between the groups. Prothrombin time ratio, concentrations of d-dimer, thrombin-antithrombin complex, and intercellular adhesion molecule-1 increased only in the control group and polymorphonuclear leukocyte elastase, IL-6, tumor necrosis factor-alpha, and vascular cell adhesion molecule-1 increased in both groups. They were significantly less in the antithrombin group except for intercellular adhesion molecule-1. In conclusion, antithrombin could decrease hypercoagulation and inflammatory activation during abdominal aortic aneurysm surgery, which may decrease adverse events.
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PMID:Antithrombin can modulate coagulation, cytokine production, and expression of adhesion molecules in abdominal aortic aneurysm repair surgery. 1655 89

Cysteinyl leukotrienes (cysLT), i.e., LTC4, LTD4, and LTE4, are lipid mediators derived from the 5-lipoxygenase pathway, and the cysLT receptors cysLT1-R/cysLT2-R mediate inflammatory tissue reactions. Although endothelial cells (ECs) predominantly express cysLT2-Rs, their role in vascular biology remains to be fully understood. To delineate cysLT2-R actions, we stimulated human umbilical vein EC with LTD4 and determined early induced genes. We also compared LTD4 effects with those induced by thrombin that binds to protease-activated receptor (PAR)-1. Stringent filters yielded 37 cysLT2-R- and 34 PAR-1-up-regulated genes (>2.5-fold stimulation). Most LTD4-regulated genes were also induced by thrombin. Moreover, LTD4 plus thrombin augmented gene expression when compared with each agonist alone. Strongly induced genes were studied in detail: Early growth response (EGR) and nuclear receptor subfamily 4 group A transcription factors; E-selectin; CXC ligand 2; IL-8; a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif 1 (ADAMTS1); Down syndrome critical region gene 1 (DSCR1); tissue factor (TF); and cyclooxygenase 2. Transcripts peaked at approximately 60 min, were unaffected by a cysLT1-R antagonist, and were superinduced by cycloheximide. The EC phenotype was markedly altered: LTD4 induced de novo synthesis of EGR1 protein and EGR1 localized in the nucleus; LTD4 up-regulated IL-8 formation and secretion; and LTD4 raised TF protein and TF-dependent EC procoagulant activity. These data show that cysLT2-R activation results in a proinflammatory EC phenotype. Because LTD4 and thrombin are likely to be formed concomitantly in vivo, cysLT2-R and PAR-1 may cooperate to augment vascular injury.
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PMID:Cysteinyl leukotriene 2 receptor and protease-activated receptor 1 activate strongly correlated early genes in human endothelial cells. 1660 35

The notion that microvascular abnormalities contribute to deleterious changes in the Alzheimer's disease (AD) brain is supported by work from our laboratory and others demonstrating biochemical and functional alterations of the microcirculation in AD. The objective of this study is to determine whether levels of neurotoxic (thrombin) and inflammatory (interleukin 8 (IL-8), integrins alphaVbeta3 and alphaVbeta5) proteins are altered in microvessels isolated from AD patients compared to levels in vessels obtained from non-demented age-matched controls. We also evaluate in AD and control microvessels expression of the transcription factor hypoxia-inducible factor 1-alpha(HIF1-alpha), which regulates pro-inflammatory gene expression, and the regulation of HIF1-alpha expression by thrombin in cultured brain endothelial cells. Our results indicate that in AD there are high levels of expression of the neurotoxic protease thrombin and the inflammation-associated proteins IL-8 and alphaVbeta3 and alphaVbeta5 integrins. HIF1-alpha is higher in AD microvessels compared to control and thrombin treatment of cultured brain endothelial cells results in increased expression of HIF1-alpha. These data suggest that in AD the cerebral microcirculation is a source of neurotoxic and inflammatory mediators and as such contributory to pathologic processes ongoing in the AD brain.
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PMID:Thrombin and inflammatory proteins are elevated in Alzheimer's disease microvessels: implications for disease pathogenesis. 1662 34

It was reported that thrombin could induce IL-8 secretion from human dermal fibroblasts (HDFs) through activation of proteinase activated receptor (PAR)-1. However, little is known of intracellular signaling pathways involved in the event. In the present study, expression of PARs in primarily cultured HDFs was determined by flow cytometry analysis and reverse transcription polymerase chain reaction (RT-PCR), levels of IL-8 were determined by using ELISA and signaling pathways were examined by using Western blot. It was found that HDFs express PAR-1 and PAR-3, and thrombin induces approximately 7.4-fold increase in IL-8 secretion from HDFs. Hirudin and a PAR-1 blocking antibody completely abolish the action of thrombin. It was also found that PD98059, a mitogen-activated protein kinase (MAPK) pathway inhibitor and U0126, an inhibitor of extracellular signal-regulated kinase (ERK) blocks thrombin-induced phosphorylation of ERK1/2 and IL-8 secretion, indicating the involvement of MAPK/ERK signaling pathway in thrombin-induced IL-8 secretion. p38 MAPK pathway appears also being involved as SB203580, a selective inhibitor of p38 MAPK inhibit phosphorylation of p38 MAPK and thrombin-induced IL-8 secretion. Furthermore, Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathway, but not phosphotidylinositol 3-kinase (PI3K)/Akt signaling pathway may also be activated by thrombin. In conclusion, thrombin potently induce IL-8 release via PAR-1 from HDFs. Thrombin elicited IL-8 release is predominantly conducted through MAPK/ERK and p38 MAPK signaling pathways. Discovery of the signaling pathways of thrombin in HDFs may help to understand the role of thrombin in inflammation and tissue remodeling.
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PMID:Induction of interleukin-8 secretion and activation of ERK1/2, p38 MAPK signaling pathways by thrombin in dermal fibroblasts. 1669 90


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