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)

Kaposi sarcoma (KS) is a multifocal angioproliferative neoplasm strictly dependent on angiogenic growth factors and cytokines and invariably associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV or HHV8). A G protein-coupled receptor encoded by KSHV (vGPCR) is able to initiate KS-like tumors when targeted to the vascular endothelium of mice. Analogous to human KS, vGPCR sarcomagenesis involves the paracrine secretion of angiogenic growth factors and proinflammatory molecules from vGPCR-expressing cells. Here we demonstrate that vGPCR up-regulates expression and secretion of critical KS cytokines by stimulating key transcription factors, including nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), and nuclear factor of activated T cells (NFAT), through the activation of the small G protein Rac1. Inhibition of Rac1 blocked vGPCR-induced transcription and secretion of KS cytokines, including interleukin-6 (IL-6), IL-8, and growth-regulated oncogene alpha (GROalpha), in vitro and reduced vGPCR tumorigenesis in vivo. Moreover, endothelial-specific infection with the constitutively active Rac1QL induced vascular lesions in mice that were remarkably similar to early vGPCR experimental lesions. These results identify Rac1 as a key mediator of vGPCR paracrine neoplasia, suggesting that this small G protein and its downstream effectors may represent suitable therapeutic targets for the treatment of KS.
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PMID:The small GTPase Rac1 links the Kaposi sarcoma-associated herpesvirus vGPCR to cytokine secretion and paracrine neoplasia. 1523 71

Inflammation occurs in response to tissue injury or the presence of foreign antigens and is important in the mobilization of specific immunologic and nonimmunologic defenses against injury. The vascular endothelium is altered to allow immune competent cells to access the interstitial space. Muscle and visceral proteins are catabolized and the amino acids are used either to supply energy or as substrates for the production of acute-phase proteins that play a role in defense. Restoration of muscle mass is impaired while inflammation is on going. Lipids are mobilized. Although serving a vital role in allowing host survival from acute injury or infection, if unimpeded, or if triggered inappropriately, the acute-phase response may instead lead to increased vascular injury and progressive loss of muscle and visceral protein pools causing malnutrition. Markers of inflammation (C reactive protein [CRP] or interleukin-6 [IL-6] levels) are associated with cardiovascular risk in the general population and in dialysis patients. Hypoalbuminemia also is associated with cardiovascular risk in dialysis patients. Although albumin is considered a marker of nutrition, changes in albumin levels are associated with increased levels of acute-phase proteins. Persistent changes in albumin levels are caused by reduced albumin synthesis associated with inflammation and not decreased normalized protein catabolic rate. The cause(s) of inflammation must be identified and treated to resolve malnutrition and reduce cardiovascular risk.
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PMID:Inflammation: cause of vascular disease and malnutrition in dialysis patients. 1549 Apr 5

Interleukin-4 (IL-4)-mediated pro-oxidative and pro-inflammatory vascular environments have been implicated in the pathogenesis of atherosclerosis. The cellular and molecular regulatory mechanisms underlying this process, however, are not fully understood. In the present study, we employed GeneChip microarray analysis to investigate global gene expression patterns in human vascular endothelial cells after treatment with IL-4. Our results showed that mRNA levels of a total of 106 genes were significantly up-regulated and 41 genes significantly down-regulated with more than a 2-fold change. The majority of these genes are critically involved in the regulation of inflammatory responses, apoptosis, signal transduction, transcription factors, and metabolism; functions of the remaining genes are unknown. The changes in gene expression of selected genes related to inflammatory reactions, such as vascular cell adhesion molecule-1 (VCAM-1), E-selectin, monocyte chemoattractant protein-1 (MCP-1), and interleukin-6 (IL-6), were verified by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) analyses. IL-4 treatment also significantly increased the adherence of inflammatory cells to endothelial cell monolayers in a dose-dependent manner. These results may help determine the molecular mechanisms of action of IL-4 in human vascular endothelium. In addition, a better understanding of IL-4-induced vascular injury at the level of gene expression could lead to the identification of new therapeutic strategies for atherosclerosis.
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PMID:Gene expression profile in interleukin-4-stimulated human vascular endothelial cells. 1550 79

Chronic obstructive pulmonary disease (COPD) is a risk factor for development of cardiovascular events, independent of smoking. The mechanisms are unclear, but systemic inflammation associated with COPD may contribute to this cardiovascular risk. Similar to cigarette smoking, exposure to particulate air pollution is associated with an increase in the mortality and morbidity from respiratory and cardiovascular diseases. The exposure of humans to high levels of ambient particles stimulates the bone marrow and the release of neutrophils, band cells, and monocytes into the circulation. This bone marrow simulation is associated with increased levels of circulating interleukin-1beta and interleukin-6, similar to cigarette smoking. In animals, exposure to particulate matter accelerates the transit of neutrophils and monocytes in bone marrow and expands the leukocyte pool size. This systemic inflammatory response to particle inhalation causes endothelial activation and upregulation adhesion molecules that are critically important in leukocyte recruitment into atherosclerotic plaques. Exposure to particles also causes disease progression and destabilization of atherosclerotic plaques in rabbits that develop atherosclerosis naturally. We suspect, therefore, that the systemic inflammatory responses described activate vascular endothelium and cause progression and instability of atherosclerotic plaques. We speculate that this mechanism may contribute to the cardiovascular morbidity and mortality associated with COPD.
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PMID:Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. 1611 70

Semicarbazide-sensitive amine oxidase (SSAO) resides on the vascular endothelium and smooth muscle cell surface and is capable of deaminating short chain aliphatic amines and producing toxic aldehydes and hydrogen peroxide. The enzyme, also known as a vascular adhesion protein-1, is involved in the inflammation process. This intriguing protein with dual functions is increased in the serum of diabetic and heart failure patients. In the present study we assessed the involvement of SSAO in a lipopolysaccharide-induced pulmonary inflammation model using transgenic mice that overexpress human vascular adhesion protein-1. Overexpression of SSAO activity increased the formation of protein-formaldehyde deposits in tissues. Lysine residues of proteins were the primary targets for cross-linkage with formaldehyde derived from deamination of methylamine. Lipo-polysaccharide-induced increases in inflammatory cells in the bronchoalveolar lavage (BAL) fluid were significantly higher in the transgenic than in the nontransgenic mice. BAL cell counts were also higher in the untreated transgenic than in nontransgenic mice. Blocking SSAO activity with a selective inhibitor significantly reduced the number of neutrophils as well as levels of macrophage inflammatory protein-1alpha, granulocyte colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-6 in the BAL fluid. Inhalation of methylamine also increased BAL neutrophil counts. Together, these results suggest a role for SSAO-mediated deamination in pulmonary inflammation.
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PMID:Involvement of semicarbazide-sensitive amine oxidase-mediated deamination in lipopolysaccharide-induced pulmonary inflammation. 1650 87

C-type natriuretic peptide (CNP) is expressed in the vascular endothelium. It is not known whether CNP is specifically increased in patients with idiopathic left ventricular systolic dysfunction (ILVDys) with or without overt heart failure, and whether in these patients it is related with indicators of myocardial and/or endothelial/microvascular impairment. We determined plasma CNP levels in 51 ILVDys and in 60 controls. We observed a significant increase in patients with (7.0+/-0.9 pg/ml) or without (6.1+/-0.53 pg/ml) overt heart failure (p<0.001) in respect to controls (2.5+/-0.12 pg/ml). CNP was significantly correlated with LVEF (p<0.001), end-diastolic dimension (p<0.05), ANP (p<0.001) and BNP (p<0.001), interleukin-6 (p<0.001), total cholesterol (p<0.05), low-density lipoprotein (p=0.05), ratio total cholesterol/ high-density lipoprotein (p=0.05) and, in a subgroup of patients, with abnormal vasodilating capacity of the coronary microcirculation. In conclusion, CNP is activated in patients with LV dysfunction but without coronary artery disease, independently of the presence of overt heart failure and in tune with the extent of myocardial functional involvement. In these patients CNP is also related with both systemic and coronary indicators of endothelial/microvascular damage.
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PMID:Increased levels of C-type natriuretic peptide in patients with idiopathic left ventricular dysfunction. 1742 80

It has been shown that stromal-vascular fraction isolated from adipose tissues contains an abundance of CD34+ cells. Histological analysis of adipose tissue revealed that CD34+ cells are widely distributed among adipocytes and are predominantly associated with vascular structures. The majority of CD34+ cells from freshly isolated stromal-vascular fraction were CD31-/CD144- and could be separated from a distinct population of CD34+/CD31+/CD144+ (endothelial) cells by differential attachment on uncoated plastic. The localization of CD34+ cells within adipose tissue suggested that the nonendothelial population of these cells occupied a pericytic position. Analysis of surface and intracellular markers of the freshly isolated CD34+/CD31-/CD144- adipose-derived stromal cells (ASCs) showed that >90% coexpress mesenchymal (CD10, CD13, and CD90), pericytic (chondroitin sulfate proteoglycan, CD140a, and CD140b), and smooth muscle (alpha-actin, caldesmon, and calponin) markers. ASCs demonstrated polygonal self-assembly on Matrigel, as did human microvascular endothelial cells. Coculture of ASCs with human microvascular endothelial cells on Matrigel led to cooperative network assembly, with enhanced stability of endothelial networks and preferential localization of ASCs on the abluminal side of cords. Bidirectional paracrine interaction between these cells was supported by identification of angiogenic factors (vascular endothelial growth factor, hepatocyte growth factor, basic fibroblast growth factor), inflammatory factors (interleukin-6 and -8 and monocyte chemoattractant protein-1 and -2), and mobilization factors (macrophage colony-stimulating factor and granulocyte/macrophage colony-stimulating factor) in media conditioned by CD34+ ASCs, as well a robust mitogenic response of ASCs to basic fibroblast growth factor, epidermal growth factor, and platelet-derived growth factor-BB, factors produced by endothelial cells. These results demonstrate for the first time that the majority of adipose-derived adherent CD34+ cells are resident pericytes that play a role in vascular stabilization by mutual structural and functional interaction with endothelial cells.
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PMID:A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. 1796 85

Cardiovascular diseases are among the worldwide leading causes of shorter life expectancy and loss of quality of life. Thus, any influence of diet or life habits on the cardiovascular system may have important implications for public health. Most world populations consume alcoholic beverages. Since alcohol may have both protective and harmful effects on cardiovascular health, the identification of biochemical mechanisms that could explain such paradoxical effects is warranted. The vascular endothelium is the target of important mediating pathways of differential ethanol concentrations, such as oxidative stress, lipoproteins, and insulin resistance. Alcohol-induced endothelial damage or protection may be related to the synthesis or action of several markers, such as nitric oxide, cortisol, endothelin-1, adhesion molecules, tumor necrosis factor alpha, interleukin-6, C-reactive protein, and haemostatic factors. The expression of these markers is consistent with the J-shaped curve between alcohol consumption and cardiovascular health. However, there is genetic and phenotypic heterogeneity in alcohol response, and despite the apparent beneficial biochemical effects of low doses of ethanol, there is not enough clinical and epidemiological evidence to allow the recommendation to consume alcoholic beverages for abstemious individuals. Considering the potential for addiction of alcoholic beverage consumption and other negative consequences of alcohol, it would be worthwhile to identify substances able to mimic the beneficial effects of low doses of ethanol without its adverse effects.
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PMID:Alcohol consumption, cardiovascular health, and endothelial function markers. 1798 Jul 86

Rheological properties of erythrocytes from patients with high risk of cardiovascular disease (CVD) were analyzed in relation to individual patient risk factors as well as to the medication. Additionally, comparative statistical analysis was performed considering plasma concentration of the selected mediators of vascular endothelium: 6-keto-prostaglandin F(1alpha) (PGF(1alpha)), sVCAM-1 and E-selectin adhesion molecules and interleukin-6 (IL-6). It was found that antihypertensive therapy with angiotensin-converting enzyme inhibitor (ACEI) is accompanied by improvement of RBC rheology: the increase of deformability and the decrease of aggregability. This improvement is probably mediated by endothelial prostacyclin and nitric oxide which are generated by ACEI. A correlation was observed between RBC deformability/aggregability and the patient's hematocrit level, what implicates that the hematocrit level should be explicitly taken into consideration when investigating rheological properties of erythrocytes. A strong relationship was also found between the plasma concentration of sVCAM-1 and patient's age.
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PMID:Rheological properties of erythrocytes in patients with high risk of cardiovascular disease. 1850 28

The vascular endothelium may develop a proinflammatory profile with aging, but evidence is limited in humans. Expression of inflammatory proteins was determined in vascular endothelial cells (EC) obtained from peripheral veins of 24 young (23 +/- 1 years, mean +/- SE) and 36 older (63 +/- 1) healthy men and women using quantitative immunofluorescence. The older subjects had lower vascular endothelium-dependent dilation (forearm blood flow responses to acetylcholine, p < 0.05), and higher plasma concentrations of C-reactive protein, interleukin-6 (IL-6), and oxidized low-density lipoprotein (all p < 0.05), but not tumor necrosis factor-alpha (TNF-alpha). Total (O: 0.52 +/- 0.04 vs. Y: 0.33 +/- 0.05 NFkappaB/HUVEC intensity, p < 0.05) and nuclear (O: 0.59 +/- 0.04 vs. Y: 0.41 +/- 0.04) expression of nuclear factor kappa B p65 (NFkappaB), a proinflammatory gene transcription factor, was greater in EC from the older subjects (p < 0.05). EC expression of the inhibitor (of nuclear translocation) of NFkappaB (IkappaBalpha) was lower in the older subjects (O: 0.16 +/- 0.02 vs. Y: 0.24 +/- 0.03, p < 0.05), whereas IkappaB kinase (IkappaK) was not different. EC expression of the proinflammatory proteins IL-6 (O: 0.42 +/- 0.06 vs. Y: 0.29 +/- 0.03, p < 0.05), TNF-alpha (O: 0.52 +/- 0.06 vs. Y: 0.33 +/- 0.05, p < 0.05) and monocyte chemoattractant protein 1 (MCP-1) (O: 0.59 +/- 0.06 vs. Y: 0.38 +/- 0.02, p < 0.05) was greater in the older subjects, whereas cyclooxygenase 2 and the receptor for advanced glycation end-products did not differ. These findings indicate that impaired function with aging in healthy adults is associated with the development of a proinflammatory phenotype in the vascular endothelium that could be caused in part by reduced IkappaB-mediated inhibition of NFkappaB.
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PMID:Aging is associated with greater nuclear NF kappa B, reduced I kappa B alpha, and increased expression of proinflammatory cytokines in vascular endothelial cells of healthy humans. 1878 46


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