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)

Endothelial cells, as they normally exist in the vasculature as quiescent cells, perform several functions. In an inflammatory response, endothelial cells are activated to up-regulate a number of genes, including E-selectin (ELAM-1), VCAM-1, ICAM-1, interleukin (IL)-1, IL-8 and plasminogen activator inhibitor-1 (PAI-1). Very little is known about factors that regulate the activation process. We describe here that a heat-stable protein, normally present in the alpha-globulin fraction of serum, inhibits induced expression of E-selectin, ICAM-1, and VCAM-1 in vitro and also impedes the accumulation of mRNA for these molecules. Inhibition of E-selectin, the only gene tested in this respect, is at the level of transcription. At the same time, the alpha-globulins do not, under the same conditions, repress mRNA accumulation for IL-1, IL-8, or PAI-1. The effect of the inhibitor does not relate to constraints on function of nuclear-factor kappa B, the induced activity of which is not interfered with at the early time points at which the suppression of these three genes is seen.
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PMID:Selective inhibition of E-selectin, ICAM-1, and VCAM in endothelial cells. 752 66

Endothelial cell activation is achieved by the rapid, protein synthesis-independent induction of a characteristic set of genes. Because of the abundance of binding sites for the transcription factor NF-kappa B in the regulatory region of the aforementioned genes, we hypothesized that this factor might play a key role. Reactive oxygen intermediates act as second messengers in the activation of NF-kappa B. We have used the antioxidant pyrrolidine dithiocarbamate to analyze the effect of NF-kappa B inhibition on TNF alpha-induced EC activation in vitro. We show that pyrrolidine dithiocarbamate strongly reduces the TNF alpha-mediated induction of E-selectin, VCAM-1, ICAM-1, PAI-1, tissue factor, IL-8 and I kappa B-alpha. We present evidence identifying NF-kappa B as a central of EC activation. Therefore, this factor may represent a prime target for therapeutic intervention in pathologic conditions associated with EC activation such as allo- and xenograft rejection, atherosclerosis, ischemic reperfusion injury and vasculitis.
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PMID:Inhibition of NF-kappa B by pyrrolidine dithiocarbamate blocks endothelial cell activation. 754 93

Endothelial cell (EC) activation plays a key role in inflammation, thrombosis and organ rejection. Normally, EC are in a quiescent state in which their function is to prevent coagulation and thrombosis, and to participate in the regulation of leukocyte migration from the bloodstream into the tissue. Upon activation with cytokines or other stimuli, EC up-regulate a number of genes, including E-selectin (ELAM-1), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, interleukin (IL)-1, IL-8, tissue factor (TF), plasminogen activator inhibitor-1 (PAI-1), MCP-1 (monocyte chemoattractant protein-1) and endothelial cell inducible gene (ECI-6). Arachidonic acid (AA) is produced by several cell types, including EC, and acts on various cells. We report here that AA inhibits the up-regulation of some, but not all genes that are induced with EC activation in a dose-dependent manner. AA suppresses TNF-alpha, IL-1 alpha, LPS or PMA-induced E-selectin expression, as well as mRNA accumulation of E-selectin, ICAM-1 and IL-8 stimulated by TNF-alpha. The inhibition appears to be at the level of transcription. At the same time under the same conditions AA does not, repress mRNA accumulation for PAI-1, ECI-6, MCP-1 and VCAM-1. We suggest that the induced expression of AA with EC activation may result in a negative feedback loop regulating further activation.
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PMID:Selective suppression of endothelial cell activation by arachidonic acid. 876 41

Thrombin is the central bioregulatory enzyme in hemostasis and is generated in vascular beds in which inflammatory responses are ongoing. In this study, we examined the effect of thrombin, both alone and in combination with TNF, on gene expression in porcine aortic endothelial cells (EC). Thrombin (1-10 U/ml) induced increased mRNA levels of E-selectin, monocyte chemoattractant protein-1, IL-8, plasminogen activator inhibitor-1, and IkappaB-alpha. These effects were mimicked by a thrombin receptor-activating peptide; preincubation of thrombin with hirudin blocked the induction of mRNA, suggesting that the increased gene expression was due to thrombin-specific activity. Because these genes are known to contain nuclear-factor-kappaB (NF-kappaB)-binding elements in their promoter region, we next examined the ability of thrombin to activate this transcription factor. As detected by electrophoretic mobility shift assay, thrombin (10 U/ml) or thrombin receptor-activating peptide (100 microM) stimulated increased NF-kappaB-binding activity. Supershift analysis revealed that these complexes were comprised principally of the RelA (p65) and NF-kappaB1 (p50) Rel family members. Thrombin alone did not substantively increase protein levels of E-selectin despite the increase in E-selectin mRNA levels. However, thrombin (3-10 U/ml) stimulated a 10-fold enhancement in the ability of TNF (0.3-1.0 ng/ml) to induce E-selectin surface expression. Similar potentiation of TNF-induced NF-kappaB activity and E-selectin transcription by thrombin was observed in experiments utilizing luciferase reporter constructs expressed in bovine aortic EC. The ability of thrombin to potentiate TNF-induced EC activation thus provides an important mechanism by which products of the coagulation cascade may enhance cytokine-mediated inflammatory responses.
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PMID:Thrombin activates nuclear factor-kappaB and potentiates endothelial cell activation by TNF. 954 5

Inflammatory response in tissue results from a complex network of interactions between inflammatory cells (mast cells, eosinophils, basophils, macrophages) and resident cells belonging to the lung structure (like endothelial cells, fibroblasts, epithelial cells). Among structural cells, endothelial cells play a critical role. The important role of endothelium is also reflected in the fact that it occupies an area exceeding 1000 m2. Thus, endothelium is the largest and the most active paracrine organ in the body, producing potent vasoactive, procoagulant, anticoagulant, and proinflammatory substances. Endothelial cells have four key functions that alter in the process of inflammation: 1 a) Regulation and control of leukocyte traffic through the expression of adhesion molecules (selectins E and P, molecules of immunoglobulin superfamily ICAM-1, ICAM-2, VCAM); 1 b) They are also able to amplify leukocyte activation through the production of proinflammatory cytokines like IL-1, IL-6 and chemokines like IL-8 and RANTES molecules; 2) Regulation of vascular tone by production of PGI-2, EDRF/NO and elements of local renin-angiotensin system; 3) Regulation of local coagulation by controlling the production of t-PA and PAI-1; 4) Regulation of the vascular permeability. In the states of acute inflammation, the endothelial cell takes on a proinflammatory phenotype and as such becomes chemoattractant, facilitating leukocyte adhesion, activation and migration, becomes prothrombotic and demonstrates enhanced vascular permeability.
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PMID:[The role of endothelial cells in allergic inflammation reactions]. 986 70

The vascular endothelium influences not only the three classically interacting components of hemostasis: the vessel, the blood platelets and the clotting and fibrinolytic systems of plasma, but also the natural sequelae: inflammation and tissue repair. Two principal modes of endothelial behaviour may be differentiated, best defined as an anti- and a prothrombotic state. Under physiological conditions endothelium mediates vascular dilatation (formation of NO, PGI2, adenosine, hyperpolarizing factor), prevents platelet adhesion and activation (production of adenosine, NO and PGI2, removal of ADP), blocks thrombin formation (tissue factor pathway inhibitor, activation of protein C via thrombomodulin, activation of antithrombin III) and mitigates fibrin deposition (t- and scuplasminogen activator production). Adhesion and transmigration of inflammatory leukocytes are attenuated, e.g. by NO and IL-10, and oxygen radicals are efficiently scavenged (urate, NO, glutathione, SOD). When the endothelium is physically disrupted or functionally perturbed by postischemic reperfusion, acute and chronic inflammation, atherosclerosis, diabetes and chronic arterial hypertension, then completely opposing actions pertain. This prothrombotic, proinflammatory state is characterised by vaso-constriction, platelet and leukocyte activation and adhesion (externalization, expression and upregulation of von Willebrand factor, platelet activating factor, P-selectin, ICAM-1, IL-8, MCP-1, TNF alpha, etc.), promotion of thrombin formation, coagulation and fibrin deposition at the vascular wall (expression of tissue factor, PAI-1, phosphatidyl serine, etc.) and, in platelet-leukocyte coaggregates, additional inflammatory interactions via attachment of platelet CD40-ligand to endothelial, monocyte and B-cell CD40. Since thrombin formation and inflammatory stimulation set the stage for later tissue repair, complete abolition of such endothelial responses cannot be the goal of clinical interventions aimed at limiting procoagulatory, prothrombotic actions of a dysfunctional vascular endothelium.
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PMID:Endothelial function and hemostasis. 1079 71

Adipose tissue is not only a passive storage organ for excessed energy intake, it is also able to produce and release several substances with local (autocrine) and systemic (endocrine) actions. An up-to-date review of our knowledge in this area is given here. Several of the compounds deriving from adipose tissue have been shown to play a role in obesity-related health complications. The production of cytokines (TNF-alpha, IL-6, IL-8) is implicated in the development of insulin resistance and atherosclerosis. All elements in the renin-angiotensin system are produced in adipose tissue, which is thus related to hypertension. The production of PAI-1 could be related to enhanced thrombogenesis. The release of the compounds described is generally higher from adipocytes in the visceral depot, which could explain the close association between this depot and health complications.
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PMID:[Fatty tissue as a secretory organ. Significance for obesity-related diseases]. 1140 68

Resistin, also known as Fizz3 or ADSF, is a protein found in murine adipose tissue and inflammatory lung exudates. The present studies found that resistin was released by explants of human adipose tissue but the release was quite variable ranging from 3 to 158 ng/g over 48 h. The release of resistin was 250% greater by explants of omental than by explants of human subcutaneous abdominal adipose tissue. Resistin release by adipocytes was negligible as compared to that by the non-fat cells of adipose tissue. Leptin formation by adipocytes was 8-fold greater than its formation by the non-fat cells, while the formation of PAI-1 by adipocytes was 38% of that by the non-fat cells. The conversion of glucose to lactate as well as the formation of PGE(2) and IL-8 was approximately 15% of that by the non-fat cells. In contrast the release of IL-6 and IL-1beta by adipocytes was 4-7% of that by the non-fat cells while the formation of resistin and IL-10 by adipocytes was 2% of that by non-fat cells. The release of adiponectin by explants ranged from 1000 to 5000 ng/g over 48 h but did not correlate with that of resistin. The present data suggest that resistin release by explants of human adipose tissue in primary culture is largely derived from the non-fat cells present in the explants.
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PMID:Resistin release by human adipose tissue explants in primary culture. 1250 2

The endothelium is the primary barrier to leukocyte recruitment at sites of inflammation. Neutrophil recruitment is directed by transendothelial gradients of IL-8 that, in vivo, are bound to the endothelial cell surface. We have investigated the identity and function of the binding site(s) in an in vitro model of neutrophil transendothelial migration. In endothelial culture supernatants, IL-8 was detected in a trimolecular complex with heparan sulfate and syndecan-1. Constitutive shedding of IL-8 in this form was increased in the presence of a neutralizing Ab to plasminogen activator inhibitor-1 (PAI-1), indicating a role for endothelial plasminogen activator in the shedding of IL-8. Increased shedding of IL-8/heparan sulfate/syndecan-1 complexes was accompanied by inhibition of neutrophil transendothelial migration, and aprotinin, a potent plasmin inhibitor, reversed this inhibition. Platelets, added as an exogenous source of PAI-1, had no effect on shedding of the complexes or neutrophil migration. Our results indicate that IL-8 is immobilized on the endothelial cell surface through binding to syndecan-1 ectodomains, and that plasmin, generated by endothelial plasminogen activator, induces the shedding of this form of IL-8. PAI-1 appears to stabilize the chemoattractant form of IL-8 at the cell surface and may represent a therapeutic target for novel anti-inflammatory strategies.
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PMID:Plasminogen activator inhibitor-1 supports IL-8-mediated neutrophil transendothelial migration by inhibition of the constitutive shedding of endothelial IL-8/heparan sulfate/syndecan-1 complexes. 1290 11

Acute and chronic hyperglycemia are proinflammatory states, but the status of proinflammatory cytokines and markers of oxidative stress and cardiovascular risks is not known in hyperglycemic crises of diabetic ketoacidosis (DKA) and nonketotic hyperglycemia (NKH). We studied 20 lean and 28 obese patients with DKA, 10 patients with NKH, and 12 lean and 12 obese nondiabetic control subjects. We measured 1) proinflammatory cytokines (tumor necrosis factor-alpha, interleukin [IL]-6, IL1-beta, and IL-8), 2) markers of cardiovascular risk (C-reactive protein [CRP], homocysteine, and plasminogen activator inhibitor-1 [PAI-1]), 3) products of reactive oxygen species (ROS; thiobarbituric acid [TBA]-reacting material, and dichlorofluorescein [DCF]), and 4) cortisol, growth hormone (GH), and free fatty acids (FFAs) on admission (before insulin therapy) and after insulin therapy and resolution of hyperglycemia and/or ketoacidosis. Results were compared with lean and obese control subjects. Circulating levels of cytokines, TBA, DCF, PAI-1, FFAs, cortisol, and GH on admission were significantly increased two- to fourfold in patients with hyperglycemic crises compared with control subjects, and they returned to normal levels after insulin treatment and resolution of hyperglycemic crises. Changes in CRP and homocysteine in response to insulin therapy did not reach control levels after resolution of hyperglycemia. We conclude that DKA and NKH are associated with elevation of proinflammatory cytokines, ROS, and cardiovascular risk factors in the absence of obvious infection or cardiovascular pathology. Return of these values to normal levels with insulin therapy demonstrates a robust anti-inflammatory effect of insulin.
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PMID:Proinflammatory cytokines, markers of cardiovascular risks, oxidative stress, and lipid peroxidation in patients with hyperglycemic crises. 1527 89


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