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)

The fibrinolytic potential of the endothelial cells gives important antithrombotic properties to the vascular wall. Thrombosis is a frequent complication to atherosclerosis and other conditions where inflammatory mediators are present in the vascular wall. Inflammatory agents like lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF alpha) have been demonstrated to modulate the expression of fibrinolytic factors in cultured endothelial cells. In the present study the expression of tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) antigen in conditioned medium from cultured human umbilical vein (HUVEC) and human saphenous vein (HSVEC) endothelial cells was investigated under basal conditions and after stimulation with LPS, TNF alpha, interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) alone or in combinations. Stimulation with LPS or TNF alpha increased the expression of PAI-1, u-PA and PAI-2 in HUVEC and HSVEC, while the t-PA response differed between the two cell types. The effects of TNF alpha were modulated by IFN-gamma but not by IL-6. The increased expression of u-PA after stimulation with TNF alpha was reduced by IFN-gamma. In contrast, TNF alpha-induced expression of PAI-2 was synergistically increased by addition of IFN-gamma. These effects of IFN-gamma represent additional mechanisms by which inflammatory mediators may turn the fibrinolytic potential of the endothelium in a prothrombotic direction.
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PMID:Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. 777 58

Human apolipoprotein E is a plasma lipoprotein that appears to play an important protective role in the development of atherosclerosis. While little is known about the regulation of apoE, recent studies have shown that cytokines repress apoE synthesis both in vivo and in vitro. Furthermore, we have recently shown that the endogenous apoE gene is negatively regulated by the nuclear trans-repressor BEF-1 in the human HepG2 cell line. In this study we demonstrate that treatment of HepG2 cells with the cytokine interleukin-1 and interleukin-6 resulted in the induction of an isoform of BEF-1, designated B1. The induction of the B1 isoform could be blocked by the protein kinase inhibitor staurosporine, suggesting that B1 is a phosphorylated form of BEF-1. As further support, the B1 isoform could also be induced by phorbol ester, and subsequently inhibited by staurosporine, implicating a role for protein kinase C-mediated phosphorylation. Quantitation of the levels of the BEF-1 isoforms, and studies in the presence of cyclohexamide, provided evidence for the phosphorylation of an existing intracellular pool of BEF-1, with no change in the total intracellular level. Under conditions that generated increased levels of the B1 isoform, there was a concomitant and proportional decrease in the level of apoE mRNA. The effect did not appear to be the result of improved binding to the apoE regulatory region as the DNA binding affinity of B1 was identical to native BEF-1. Our data suggest that the regulation of apoE by BEF-1 is modulated by differential phosphorylation, possibly through the protein kinase C pathway.
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PMID:Trans-repressor BEF-1 phosphorylation. A potential control mechanism for human ApoE gene regulation. 861 16

Serum amyloid A (SAA) is a plasma protein which has been associated with several diseases, including amyloidosis, arthritis, and atherosclerosis, and its abnormal expression, particularly in nonhepatic cells, is implicated in the pathogenesis of these diseases. Transfection and DNA-binding studies were performed to investigate the mechanism controlling cytokine-induced, nonhepatic expression of the SAA gene. We have identified a novel promoter, located between positions -280 and 224, that confers interleukin-6 (IL-6) inducibility to an SAA-chloramphenicol acetyltransferase reporter gene in both nonhepatic and hepatic cells. DNase I protection assays revealed, within this region, three homologous highly pyrimidine rich octanucleotide sequence motifs, termed SAA-activating sequences (SAS). Specific mutations within these three SAS motifs severely reduced IL-6-mediated induction of the reporter gene in transfected nonhepatic cells but not in liver cells. A nuclear factor activated by IL-6 in both hepatic and nonhepatic cells efficiently interacts with the SAS. The induction kinetics and cycloheximide sensitivity of this SAS-binding factor (SAF) suggested that de novo synthesis of this factor itself or an activator protein is essential. Loss of DNA-binding ability as a result of in vitro dephosphorylation, induction of SAA-chloramphenicol acetyltransferase reporter gene activity in the presence of genistein, a protein kinase inhibitor, further indicate that a phosphorylation step is necessary for the activation of SAF. Our results suggest that SAF is a key regulator of cytokine-mediated SAA gene expression in some nonhepatic cells.
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PMID:A novel cis-acting element is essential for cytokine-mediated transcriptional induction of the serum amyloid A gene in nonhepatic cells. 865 33

The small leucine-rich proteoglycan biglycan is involved in several physiological and pathophysiological processes through the ability of its core protein to interact with other extracellular matrix molecules and transforming growth factor-beta (TGF-beta). To learn more about the regulation of biglycan core protein expression, we have cloned and sequenced 1218 base pairs from the 5'-flanking region of the human biglycan gene, demonstrated functional promoter activity, and investigated the molecular mechanisms through which various agents modulate its transcriptional activity. Sequencing revealed the presence of several cis-acting elements including multiple AP-2 sites and interleukin-6 response elements, a NF-kappaB site, a TGF-beta negative element, and an E-box. The TATA and CAAT box-lacking promoter possesses many features of a growth-related gene, e.g. a GC-rich immediate 5' region, many Sp1 sites, and the use of multiple transcriptional start sites. Transient transfections of the tumor cell lines MG-63, SK-UT-1, and T47D with various biglycan 5'-flanking region-luciferase reporter gene constructs showed that the proximal 78 base pairs are sufficient for full promoter activity. Several agents among them interleukin-6, and tumor necrosis factor-alpha. were capable of altering biglycan promoter activity. However, in MG-63 cells, TGF-beta1 failed to increase either activity of the biglycan promoter constructs or specific transcription from the endogenous biglycan gene. Since TGF-beta1 also did not alter the stability of cytoplasmic biglycan mRNA as determined from Northern analysis after inhibition of transcription with 5,6-dichloro-1beta-D-ribofuranosylbenzimidazole, an as yet unidentified nuclear post-transcriptional mechanism was considered responsible for the TGF-beta effect in this cell type. These results might help to elucidate the molecular pathways leading to pathological alterations of biglycan expression observed in atherosclerosis, glomerulonephritis, and fibrosis.
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PMID:Transcriptional regulation of the human biglycan gene. 866 74

Current evidence indicates that plasma fibrinogen is synthesized by the liver; that genetic and environmental factors regulate plasma fibrinogen levels; that interleukin-6 (IL-6) affects the synthesis of plasma fibrinogen by mechanisms involving protein kinase C, and that during the acute-phase response, monocytes generate a variety of monokines including IL-6. Certain drugs and nutrients have been reported to lower plasma fibrinogen levels. The mechanism(s) involved in this effect is poorly understood. However, since most of these substances quantitatively and/or qualitatively affect monocytes, the possibility that these drugs affect plasma fibrinogen levels via these cells should be considered. In addition to fibrinogen, IL-6 also regulates the synthesis of other acute-phase proteins. Especially when combined, major risk factors for atherosclerosis cause vascular injury that triggers inflammatory events. This raises the issue of whether high plasma fibrinogen levels are just the epiphenomenon of as yet unknown events in thrombosis and atherosclerosis. Thus, the issue to be addressed is whether high plasma fibrinogen concentrations should be lowered or should they serve to suggest strong interventions on established risk factors. As for other risk factors, fibrinogen measurements in population-based studies, in parallel with measurements of established risk factors will help define appropriate directions to be followed to gain insight into the issue and define new antithrombotic strategies.
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PMID:Drugs affecting plasma fibrinogen levels. Implications for new antithrombotic strategies. 875 5

We recently reported that tumor necrosis factor alpha is able to cause a dose-dependent and persistent reduction in gap junctional intercellular communication between primary human smooth muscle cells. In order to study whether this observed persistent reduction in gap junctional intercellular communication is a unique feature for tumor necrosis factor alpha, the present study focuses on the effects of other growth factors and cytokines on gap junctional intercellular communication. Platelet-derived growth factor AA and BB (PDGF-AA, PDGF-BB), basic fibroblast growth factor (bFGF), interleukin-6 and interferon-gamma were able to modulate gap junctional intercellular communication between primary human smooth muscle cells in vitro. However, our results demonstrate that the magnitude and nature of the observed effects are growth factor- and cytokine-specific. PDGF-AA, PDGF-BB and interleukin-6 caused a transient reduction in gap junctional intercellular communication, while bFGF induced a transient increase in gap junctional intercellular communication. Interferon-gamma was shown to be capable of causing a persistent reduction in gap junctional intercellular communication. In addition, PDGF-AA, PDGF-BB, bFGF, interleukin-6, interferon-gamma and tumor necrosis factor alpha all stimulated smooth muscle cell proliferation. These observations suggest a more complex relationship between modulation of gap junctional intercellular communication and cell proliferation than current hypotheses imply. The implications of the observed effects of growth factors and cytokines on gap junctional intercellular communication between smooth muscle cells in relation to the process of atherosclerosis is discussed.
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PMID:Modulation of intercellular communication between smooth muscle cells by growth factors and cytokines. 888 70

n-3 polyunsaturated fatty acids (PUFA) can affect several monocyte functions and the biochemistry of blood cells, thus possibly influencing the initiation of thrombosis, inflammatory disease and atherosclerosis. In this study, we have investigated the effect of dietary supplementation with n-3 PUFA ethyl esters on procoagulant activity (PCA) and interleukin-6 (IL-6) production by human mononuclear cells. Nine healthy volunteers received 4 g/d of n-3 PUFA ethyl esters (4 x 1 g capsules with at least 85% eicosapentaenoic + docosahexaenoic acid ethyl esters) for 18 weeks. Before and at the end of the treatment, mononuclear cells were obtained from peripheral citrated blood by Ficoll-Hypaque density gradient centrifugation. Cellular suspensions (10(7) cells/ml) were incubated at 37 degrees C for 4 h in the absence and presence of lipopolysaccharide (10 micrograms/ml); PCA was determined by one-stage clotting assay and IL-6 concentrations were assayed in supernatants by specific ELISA. After 18-week treatment, both unstimulated and stimulated monocyte PCA were significantly reduced by 66% and 63%, respectively (P < 0.01). Similarly, a significant inhibitory effect by n-3 PUFA treatment on basal and LPS-stimulated IL-6 monocyte production was observed (50% and 46%, respectively, P < 0.05). These data indicate that 18-week n-3 PUFA supplementation may influence monocyte activities, which play a specific role in atherosclerosis and its thrombotic complications.
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PMID:n-3 PUFA supplementation, monocyte PCA expression and interleukin-6 production. 888 56

Insulin-dependent diabetic patients with nephropathy have a high risk of cardiovascular disease. Chronic inflammation is a part of the pathogenesis of atherosclerosis, and presently we have studied the relation between the inflammatory state, measured as levels of interleukin-6 and C-reactive protein and fibrinogen in diabetic nephropathy. Thirty-three insulin-dependent diabetic patients with diabetic nephropathy (urinary albumin excretion rate (AER) > 300 mg/24-h) and 22 patients with incipient diabetic nephropathy (AER 30-300 mg/24-h) were compared with 14 non-diabetic controls and 17 diabetic patients with normal AER (<30 mg/24-h). Fibrinogen was significantly higher in diabetic nephropathy than in non-diabetic controls and diabetic patients with normal AER (median 8.1, range (5.4-15.6) mu mol/l vs. 6.6 (5.0-12.1) mu mol/l, p < 0.05, and 6.2 (5.0-9.0) mu mol/l, p < 0.005, respectively), while C-reactive protein did not deviate between groups. Interleukin-6 was significantly elevated in all insulin-dependent diabetic patients (diabetic nephropathy (3.2 (1.0-14.5) pg/ml, p < 0.005), incipient nephropathy (3.7 (1.0-22.9) pg/ml, p < 0.005) and diabetic patients with normal AER (2.7 (1.0-9.0) pg/ml, p < 0.05) compared with nondiabetic controls (1.2 (1.0-6.2) pg/ml)). When fibrinogen was adjusted for interleukin-6, C-reactive protein or both, the level of fibrinogen was still higher in patients with diabetic nephropathy than in patients without nephropathy (p < 0.05), which suggests that inflammation is not the only mechanism that increases fibrinogen levels in patients with diabetic nephropathy.
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PMID:Elevated fibrinogen and the relation to acute phase response in diabetic nephropathy. 890 98

Altered platelet morphology and function have been reported in patients with diabetes. They are likely to be associated with the pathological processes and increased risk of vascular disease seen in these patients. Mean platelet volume (MPV), platelet count, and megakaryocyte (MK) ploidy (DNA content) were measured in (1) nondiabetics with normal coronary arteries, (2) nondiabetics with coronary artery atherosclerosis, (3) diabetics without evidence of vascular complications, and (4) diabetics with vascular disease. The platelet count (+/- SD) was increased in all groups but only significantly in the diabetics with vascular disease (236 +/- 65 versus 250 +/- 54 versus 257 +/- 64 versus 295 +/- 90 [P < or = .05] x 10(9)/L, for groups, I, II, II, and IV, respectively). The MPV was significantly increased in patients with atherosclerosis (7.0 +/- 0.4 versus 8.0 +/- 1.2 [P < or = .05] versus 7.2 +/- 0.9 versus 8.1 +/- 0.9 [P < or = .05] IL). Geometric mean MK ploidy was significantly increased in all groups compared with controls (16 +/- 1.5 versus 18.7 +/- 1.8 [P < or = .05] versus 19.8 +/- 1.6 [P < or = .05] versus 20.1 +/- 2.7 [P < or = .05]). Furthermore, some patients with vascular disease and/or diabetes had a modal ploidy shift from 16 (the normal mammalian modal ploidy) to 32, with a concomitant reduction of MKs in the 8 and 16 ploidy classes. This shift was seen particularly in the diabetics with vascular disease (P = .007). Interleukin-6 (IL-6) levels were measured and were elevated in patients with atherosclerosis; the highest levels were found in the diabetic patients (0.7 +/- 0.9 versus 5.3 +/- 5.5 [P < or = .05] versus 2.5 +/- 2.8 versus 6.7 +/- 5.5 [P < or = .05] ng/L). In the diabetic patients with atherosclerosis, fibrinogen levels were also increased (2.85 +/- 0.76 versus 3.34 +/- 1.32 versus 2.43 +/- 1.50 versus 5.59 +/- 1.72 [P < or = .05] g/L). Furthermore, IL-6 levels correlated with MK ploidy (r = .45, P = .009) and fibrinogen levels (r = .5, P = .0001). This study demonstrates that patients with vascular disease, particularly diabetics, have an altered MK ploidy distribution, showing a shift toward higher ploidy in association with an increased platelet mass (count x volume). Changes in platelets in diabetes probably reflect MK changes, which themselves are a response to systemic change.
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PMID:Megakaryocyte ploidy and platelet changes in human diabetes and atherosclerosis. 910 97

In vitro-studies have shown that phospholipid hydrolysis of low density lipoproteins (LDL) by bee venom or porcine pancreatic phospholipase A2 (PLA2) leads to an increased uptake of these lipoproteins by macrophages transforming them into foam cells. Recently, a secretory phospholipase A2, group II, was detected in human atherosclerotic plaques. In order to investigate the role of this enzyme in the pathogenesis of atherosclerosis, a structurally identical human secretory PLA2 was purified from the medium of HepG2 cells stimulated with interleukin-6 and tumor necrosis factor-alpha. The activity of the purified enzyme towards the phospholipids of native and modified low density lipoproteins was compared with the activity towards Escherichia coli-membranes and other phospholipid substrates. Compared to E. coli-membranes, native LDL proved to be a poor substrate for group II PLA2. After mild oxidation induced by copper ions or by 2,2-azobis(2-amidinopropane) (AAPH), the susceptibility of LDL to phospholipid hydrolysis was found to be increased by 25 and 23%, respectively, whereas extensive copper-mediated oxidation caused a decreased hydrolysis. Aging of LDL at 6 degrees C for weeks or at 37 degrees C for hours resulted in an increase in PLA2-catalyzed phospholipid hydrolysis of up to 26-fold. LDL protected from oxidation by probucol during aging showed a lesser increase in susceptibility to phospholipid hydrolysis. Our results suggest that PLA2, group II, can increase the atherogenicity of LDL by its ability to hydrolyze the phospholipids of these lipoproteins, especially after modifications that are likely to occur in vivo.
Atherosclerosis 1997 Jul 25
PMID:Minimal oxidation and storage of low density lipoproteins result in an increased susceptibility to phospholipid hydrolysis by phospholipase A2. 924 62


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