Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor (TF) is a transmembrane glycoprotein that binds its zymogen cofactor, Factor VIIa (FVIIa) on the cell surface. Together (TF/FVIIa) they activate Factor X (FX) and Factor IX (FIX) and start the extrinsic pathway of blood coagulation. As such, the TF/FVIIa complex plays an important role in normal physiology as well as in thrombotic diseases such as unstable angina (UA), disseminated intravascular coagulation (DIC), and deep vein thrombosis (DVT). In addition to its function as an initiator of coagulation, TF/FVIIa plays an important role in inflammation. Expression of TF on the cell surface and its appearance as a soluble molecule are characteristic features of acute and chronic inflammation in conditions such as sepsis and atherosclerosis. Here we demonstrate that BCX-3607, a small molecule potent inhibitor of TF/FVIIa, reduces thrombus weight in an animal model of DVT. BCX-3607 also decreases the level of interleukin-6 (IL-6) in a LPS-stimulated mouse model of endotoxemia. Additionally, in vitro studies indicate that BCX-3607 blocks the generation of TF/FVIIa-induced IL-8 mRNA in human keratinocytes and reduces the TF/FVIIa-mediated generation of IL-6 and IL-8 in human umbilical vein endothelial cells (HUVEC). Therefore, BCX-3607 might block the TF/FVIIa-mediated coagulation and inflammation associated with pathological conditions.
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PMID:The antithrombotic and anti-inflammatory effects of BCX-3607, a small molecule tissue factor/factor VIIa inhibitor. 1637 35

We hypothesized that infusion of recombinant human antithrombin without concomitant heparin would have dose-dependent anticoagulant properties and potentially decrease endotoxin (lipopolysaccharide [LPS])-induced cytokine production. This was a randomized, double-blind, placebo-controlled study in parallel groups enrolling 30 healthy male volunteers. The active treatment groups received infusions of recombinant human antithrombin to increase antithrombin levels to 200% and 500% before infusion of 2 ng/kg endotoxin (LPS). Infusion of antithrombin dose-dependently decreased coagulation (P < .01 by repeated-measures ANOVA): peak levels of prothrombin fragment (1.8 nmol/L [95% confidence interval (CI), 1.3-2.3 nmol/L] in the 500% antithrombin group and 4.4 nmol/L [95% CI, 2.7-6.2 nmol/L] in the placebo group at 4 hours), thrombin antithrombin complexes (12 microg/L [95% CI, 8-16 microg/L] in the 500% antithrombin group and 34 microg/L [95% CI, 20-48 microg/L] in the placebo group at 4 hours), and D-dimer (0.2 microg/L [95% CI, 0.1-0.2 microg/L] in the 500% antithrombin group and 0.5 microg/L [95% CI, 0.4-0.7 microg/L] in the placebo group). Recombinant human antithrombin decreased peak interleukin-6 levels by 40% (222 pg/mL [95% CI, 148-295 pg/mL] and 216 pg/mL [95% CI, 112-320 pg/mL] in the 500% and 200% antithrombin groups, respectively, versus 357 pg/mL [95% CI, 241-474 pg/mL] in the placebo group; P < .001 by ANOVA). Finally, infusion of recombinant human antithrombin rapidly and transiently decreased neutrophil counts (by 19% [95% CI, 8%-30%] in the 500% antithrombin group versus 6% [95% CI, 1%-10%] in the placebo group, P = .002 by Kruskal-Wallis ANOVA) and monocyte counts (by 30% [95% CI, 16%-44%] in the 500% antithrombin group and 18% [95% CI, 9%-28%] in the 200% antithrombin group versus 8% [95% CI, 5%-20%] in the placebo group, P = .04) before LPS challenge, indicating that recombinant human antithrombin directly interacts with these leukocyte subsets. In summary, recombinant human antithrombin dose-dependently inhibited tissue factor-triggered coagulation. Effects on leukocytes and inhibition of interleukin-6 release seem to represent specific pharmacodynamic properties of recombinant human antithrombin.
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PMID:Recombinant human antithrombin inhibits thrombin formation and interleukin 6 release in human endotoxemia. 1641 39

The traditional function attributed to white adipose tissue of energy storage in the form of triglycerides has been challenged by results from recent studies, showing that adipose tissue is, in fact, a highly active metabolic and endocrine organ. A radical change in perspective followed the discovery of a large number of proteins secreted from white adipocytes, such as leptin, resistin, adiponectin, adipsin, acylation-stimulating protein, angiotensinogen, tumour necrosis factor a, interleukin-6, retinol-binding protein, plasminogen activator inhibitor-1, tissue factor, fasting-induced adipose factor, fibrinogen/angiopoetin-related protein, and metallothionein. The effects of specific proteins may be either autocrine or paracrine, meaning that they might act in adipose tissue itself or in more distant target tissues. Some of these proteins induce insulin resistance, some play a role in glucose and lipid metabolism, some are inflammatory cytokines, while others are involved in vascular haemostasis. The key challenges for future investigations of adipose tissue's secretory functions will be to identify all of its secreted proteins, to establish the function of each secreted protein, and to assess the pathophysiological consequences of changes in adipocyte protein production due to problems, such as obesity, fasting, or diabetes mellitus type 2.
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PMID:[Adipose tissue as an endocrine organ]. 1664 Jan 91

Recent human studies reveal that hyperglycemia induces procoagulant and antifibrinolytic effects in blood that may contribute to a greater risk of arterial thrombosis, but the direct relationship between high blood glucose levels and thrombosis has not yet been investigated. We performed a number of experiments to clarify whether hyperglycemia was causally related to arterial thrombosis and whether the combined stimulus of hyperglycemia and inflammation would enhance the thrombotic effect. In a model of ferric-chloride-induced carotid artery thrombosis, hyperglycemia did not influence the time to occlusion in mice pretreated with streptozotocin, but the rate of thrombus formation was accelerated. This effect was associated with increased thrombin generation and could not be explained by changes in vessel-wall tissue factor activity. The prothrombotic effect of hyperglycemia was assessed in a separate experiment, showing that collagen/thrombin-induced platelet procoagulant activity was increased in hyperglycemic mice. The effect of inflammation was studied by injecting a low dose of endotoxin that caused a systemic inflammatory state after 24 h (increased plasma levels of tumor necrosis factor alpha, interleukin-6 and monocyte chemotactic protein 1 in diabetic and nondiabetic mice) associated with a mild delay in thrombus formation. This reduced rate of thrombus formation was attenuated by hyperglycemia. Together, these data establish a discrete but clear contribution of hyperglycemia in experimental arterial thrombosis.
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PMID:Hyperglycemia accelerates arterial thrombus formation and attenuates the antithrombotic response to endotoxin in mice. 1789 Sep 50

1. Blood-derived monocytes/macrophages within the intima of the arterial wall are the main source of inflammatory cytokines and factors contributing to lesion growth, plaque instability and thrombotic events. In the present study, we assessed the hypothesis that mRNA expression levels of candidate genes of atherosclerosis in circulating CD14(+) blood monocytes are associated with coronary heart disease (CHD). 2. We investigated mRNA expression levels using reverse transcription-polymerase chain reaction of genes involved in cholesterol uptake (macrophage scavenger receptor (MSR1), scavenger receptor class B member 1 (SRB1), lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX1), CD36, LDL receptor (LDLR)), reverse cholesterol transport (apolipoprotein E (ApoE), ATP-binding cassette sub-family A member 1 (ABCA1)) and inflammation (tumour necrosis factor-alpha (TNF-alpha), macrophage inflammatory protein-1alpha (MIP-1alpha), interleukin-6 (IL-6), tissue factor) in CD14(+) monocytes from 119 consecutively recruited patients and found that median CD36 mRNA expression levels were significantly increased in patients with CHD compared with controls (111 x 10(3) vs 96 x 10(3) copies/10(6) copies beta-actin, respectively; n = 79 and 40, respectively; P < 0.05), despite a high interindividual variability in gene expression. 3. A common T --> C polymorphism (rs2151916) located only 14 bp upstream of the upstream transcriptional start site did not influence CD36 expression. 4. Expression levels of the other candidate genes investigated in the present study did not show any statistically significant differences between patients with CHD and controls. 5. We conclude that CD36 mRNA expression is significantly increased in patients with CHD and may serve as an indicator of CHD burden.
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PMID:CD36 mRNA expression is increased in CD14+ monocytes of patients with coronary heart disease. 1806 91

It has been established that inflammation and enhanced pro-coagulant activity are associated with the pathogenesis of atherosclerotic vascular disease. We evaluated and compared the contributions of the factor (F)XIa and tissue factor (TF) activity in plasma of patients with coronary artery disease (CAD). Citrate plasma was obtained prior to therapy from 53 patients with stable angina (29 with a history of previous myocardial infarction; CAD-MI) and 30 with acute coronary syndrome (ACS) within 12 hours from pain onset. Four ACS patients treated with heparin were excluded. FXIa and TF activity were determined in clotting assays based upon the prolongation of clotting time by inhibitory monoclonal antibodies. Twenty-five of 26ACS patients (96%) and 22 of 29 CAD-MI patients (76%) had quantifiable FXIa (50 +/- 33 and 42 +/- 45pM, respectively). Ten of 26 (38%) ACS patients and only three of 53 (6%) stable CAD patients showed TF activity (<0.4pM). No FXIa or TF activity was observed in age-matched healthy controls (n = 12). For both CAD-MI and ACS patients, there were correlations (p < 0.05) between FXIa and interleukin-6 (R(2) = 0.59 and 0.39, respectively) and between FXIa and TAT (R(2) = 0.64 and 0.63, respectively). In conclusion, the majority of ACS and CAD-MI patients have circulating FXIa that correlates with markers of coagulation and inflammation.
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PMID:Factor XIa and tissue factor activity in patients with coronary artery disease. 1821 46

We have investigated the use of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) as an alternative to a selection of late-stage functional bioassays for determination of the potency of preparations of vascular endothelial growth factor (VEGF). Responses were measured in cultures of human umbilical vein endothelial cells (HUVECs). Late-stage responses measured were cell survival and proliferation, and production of interleukin-8 (IL-8), interleukin-6 (IL-6), and tissue factor. The dose-response range was similar across the assays, increasing from 2 ng/mL VEGF and reaching a maximum between 30 ng/mL and 125 ng/mL VEGF. A number of VEGF-induced mRNA species demonstrated dose-response curves suitable for VEGF potency determination. IL-8 mRNA induction after 45 min incubation with VEGF, which showed maximal responses between 15.6 ng/mL and 62.5 ng/mL VEGF, was selected for further characterization. This gene-expression bioassay was robust across a range of cell seeding densities and could be used for samples processed immediately following incubation with VEGF and for cell lysates stored at -80 degrees C for 3 months. We also compared this gene-expression bioassay and the assays of late-stage responses in the potency measurement of the inhibitors of VEGF activity, anti-VEGF monoclonal antibody MAB293, and a VEGF soluble receptor VEGFsR1 preparation. We present a critical evaluation of the use of qRT-PCR in assaying the potency of VEGF and its inhibitors, and of the potential of this platform for measuring the potency of other biological therapeutics.
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PMID:Quantitative RT-PCR as an alternative to late-stage bioassays for vascular endothelial growth factor. 1837 35

Current thinking supports the notion that several inflammatory proteins intervene with endothelium and haemostatic factors leading to plaque formation and rupture. Of these, C-reactive protein (CRP), monocyte/macrophage colony-stimulating factor (MCSF) and interleukin-6 (IL-6) promote atherogenesis by inducing monocyte-macrophage activation, foam cell formation, platelet activation, tissue factor expression, release of other procoagulant cytokines or downregulation of atheroprotective cytokines such as interleukin 10 and transforming growth factor b-1 (TGFb-1). CRP, MSCF and IL-6 are interrelated and have been found in increased blood concentrations in CAD. Increased levels of CRP and IL-6 predict a higher cardiovascular event rate in the general population and in addition to high MCSF or low TGFb-1 predict adverse outcome in CAD patients independently of traditional risk factors. Moreover, in CAD patients, the predictive value of MCSF is additive and beyond that of CRP suggesting the need of a "multimarker approach" in assessing cardiovascular risk. Accumulating evidence supports the utility of non-invasive markers of subclinical atherosclerosis, namely carotid intimal media thickness, flow mediated dilatation of the brachial artery, augmentation index or pulse wave velocity, in the prediction of cardiovascular risk particularly in primary prevention settings. The combination of these non-invasive tests has been shown to improve their prognostic accuracy compared to each other alone. Although several therapeutic strategies like vaccination against antigens promoting atherogenesis, cyclooxygenase inhibitors, statins, and ACE inhibitors may reduce the levels of these inflammatory markers and improve the non-invasive markers of subclinical atherosclerosis, the impact on cardiovascular risk resulting from these changes is unknown. The combination of an established inflammatory marker such as CRP or a vascular marker such as IMT with novel biochemical and vascular markers of cardiovascular disease may offer additive prognostic information for adverse outcome.
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PMID:Inflammatory and non-invasive vascular markers: the multimarker approach for risk stratification in coronary artery disease. 1837 39

Ozone is a well-known oxidant air pollutant, inhalation of which can result in oxidative stress, and lead to pulmonary inflammation. The aim of this study was to evaluate the time-course events after a single ozone exposure in transcription-coupled repair defective Csb and wild type mice. Mice were exposed for 3 h to 2 ppm ozone and biological parameters related to oxidative stress and inflammation were examined in the lungs at 0, 4, 9, 24 and 48 h after exposure. In addition the procoagulant and thrombomodulin activities were explored by a combination of assays for tissue factor and thrombin generation. This study revealed a significant biological response to ozone, for both Csb and wild type mice. The onset of inflammation in Csb mice, as indicated by an increase in interleukin-6, tumor necrosis factor-alpha and total cell influx, occurred earlier compared with those seen in wild type mice. On the other hand, Csb mice showed a delayed antioxidant reaction compared with wild type mice. Both genotypes developed a procoagulant reaction characterized by a stably increased tissue factor activity and a progressive increase in thrombin generation after 2 days. These experiments have shown that ozone, a well-known toxic substance from the environment, induces not only inflammation, but also procoagulant reactions in the lungs of mice. These results have implications for understanding the systemic effects induced by oxidant air pollutants.
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PMID:Lung inflammation and thrombogenic responses in a time course study of Csb mice exposed to ozone. 1838 85

Critically ill patients often have systemic activation of both inflammatory systems and coagulation. Increasing evidence points to an extensive cross-talk between these two systems, whereby inflammation leads to activation of coagulation and coagulation considerably affects inflammatory activity. The intricate relationship between inflammation and coagulation may have major consequences for the pathogenesis of microvascular failure and subsequent multiple organ failure, as a result of severe infection and the associated systemic inflammatory response. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Activation of the coagulation system and ensuing thrombin generation is dependent on an interleukin-6-induced expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system and the antithrombin system, are shut off by proinflammatory cytokines. Modulation of inflammatory activity by activation of coagulation also occurs by various mechanisms. Activated coagulation proteases, such as the tissue factor-factor VIIa complex, factor Xa, and thrombin, can bind to protease-activated receptors on various cells, and the ensuing intracellular signaling leads to increased production of proinflammatory cytokines and chemokines. Activated protein C can bind to the protein C receptor on endothelial cells and mononuclear cells, thereby affecting NF-kappaB nuclear translocation and subsequently influencing inflammatory gene expression and inhibition of tissue factor expression on mononuclear cells. Observations in experimental models of targeted disruption of the protein C gene and restoration of the downregulated protein C pathway by administration of recombinant activated protein C support this notion.
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PMID:The role of natural anticoagulants in the pathogenesis and management of systemic activation of coagulation and inflammation in critically ill patients. 1895 86


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