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)

Lipoprotein (a) (Lp(a)) is a low density lipoprotein-like particle which contains the plasminogen-like apolipoprotein a. Lp(a) levels are elevated in patients with atherosclerotic coronary artery disease. Recent studies suggest that Lp(a) competitively inhibits plasminogen binding to the endothelial cell and interferes with surface-associated plasmin generation. In this study, we present evidence for the presence of Lp(a) in the microvasculature of inflamed tissue. In addition, we demonstrate that Lp(a) regulates endothelial cell synthesis of a major fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1). In cultured human endothelial cells, Lp(a) enhanced PAI-1 antigen, activity, and steady-state mRNA levels without altering tissue plasminogen activator activity or mRNA transcript levels. This effect was cell-specific. Although other lipoproteins did not coordinately raise PAI-1 mRNA levels in endothelial cells, low density lipoprotein treatment selectively raised the level of the 3.4-kilobase mRNA species of PAI-1 without a concomitant increase in PAI-1 activity or antigen. Endothelial cell exposure to Lp(a) did not cause generalized endothelial cell activation since the functional activity and mRNA levels for tissue factor, platelet-derived growth factor and interleukin-6 were not elevated following Lp(a) exposure. These data suggest a molecular mechanism whereby Lp(a) may support a specific prothrombotic endothelial cell phenotype, namely by increasing PAI-1 expression.
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PMID:Lipoprotein (a) regulates plasminogen activator inhibitor-1 expression in endothelial cells. A potential mechanism in thrombogenesis. 182 42

The highly metastatic human melanoma cell line BLM was transfected with the E1A or E1A + E1B regions of adenovirus 5 (Ad5). A series of progression markers, correlated with the malignant phenotype of parental BLM (including calcyclin, thymosin beta 10, plasminogen activator inhibitors types 1 and 2, urokinase type and tissue type plasminogen activators, vimentin, tissue type transglutaminase, and interleukin-6), was collectively repressed in the transfectants, whereas several control genes were not affected or even induced. The apparently coordinate repression of a set of markers by the same regulator gene, Ad5 E1A in this case, suggests the existence of one pathway under the control of a main switch and predicts that one or more as yet unidentified cellular master genes normally exert this function. A reduced oncogenicity was observed after subcutaneous inoculation of the E1A transfectants into nude mice and provides additional evidence in support of a tumor suppressor function of Ad5 E1A.
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PMID:Simultaneous suppression of progression marker genes in the highly malignant human melanoma cell line BLM after transfection with the adenovirus-5 E1A gene. 878 Jun 94

A glycoprotein (Mr = 43,000) from horseshoe crab hemocytes with antimicrobial activity against Gram-negative bacteria was purified. The internal peptide sequences coincided exactly with the deduced amino acid sequence of a cDNA clone, designated limulus factor D, which was isolated by screening a hemocyte cDNA library with an anti-human plasminogen antibody. The open reading frame codes for a precursor of factor D of 394 amino acid residues, including an NH2-terminal signal sequence. The COOH-terminal domain of factor D has significant sequence homology with the catalytic domain of mammalian serine proteases, in particular with human tissue plasminogen activator (32% identity), except for the substitution of Ser of the active site triad to Gly. Factor D has a unique NH2-terminal domain with weak sequence homology with part of the mammalian interleukin-6 receptor alpha-chain. Factor D is likely to have an important role in host defense mechanisms.
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PMID:Limulus factor D, a 43-kDa protein isolated from horseshoe crab hemocytes, is a serine protease homologue with antimicrobial activity. 897 95

We examined the promoter activity of the gene for human plasminogen (PLG) employing its 1.1 kb fragment of the 5'-flanking region inserted in front of a reporter gene. Deletion analysis revealed that a region surrounding the transcription start site was essential for the PLG expression. Since the PLG gene has three sequences for the interleukin-6 (IL-6) responsive element, we examined the effect of IL-6 on the PLG expression. IL-6 stimulation of PLG resulted in a 2.5-fold increase in its transcription. This is also true for the PLG gene of a case with dysplasminogenemia. Although the patient's gene had six mutations in the 5'-flanking region, its promoter activity was 1.8-fold that of normal PLG.
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PMID:Expression and induction by IL-6 of the normal and variant genes for human plasminogen. 902 27

Plasmin, the primary fibrinolytic enzyme, has a broad substrate spectrum and participates in other biological processes dependent upon proteolytic activity. Consequently, plasmin activity is tightly regulated by plasminogen activators and protease inhibitors. In this study, we examined whether regulation of plasminogen gene expression also might provide a new mechanism for controlling this system. We examined the effects of recombinant human interleukin-6 (rhIL-6), a pleiotropic cytokine, on plasminogen mRNA expression in primary murine hepatocytes and Hep3B human hepatoma cells. In primary hepatocytes, rhIL-6 and hydrocortisone separately increased plasminogen mRNA expression, but hydrocortisone did not markedly enhance the response to rhIL-6. Hep3B hepatoma cells exhibited more modest responses to rhIL-6. We used the polymerase chain reaction to amplify a 1,067-bp fragment of the human plasminogen promoter/5' flanking region. This fragment was cloned upstream of a luciferase reporter gene. Hep3B cells transiently transfected with this construct provided approximately 100-fold higher luciferase activity compared to cells transfected with control plasmids, and luciferase activity was increased approximately 4.5-fold when these cells were treated with rhIL-6. Furthermore, mice injected with rhIL-6 exhibited increases in hepatic plasminogen mRNA. Circulating plasminogen levels were significantly higher in the mice injected with rhIL-6 compared to mice injected with saline. Mice injected with lipopolysaccharide (an inducer of IL-6 in vivo) also showed increased hepatic plasminogen mRNA. Thus, plasminogen gene expression can be modulated by rhIL-6, suggesting a new mechanism for regulating biological systems that use plasmin.
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PMID:Regulation of plasminogen gene expression by interleukin-6. 911 83

The neurotoxicant trimethyltin (TMT) increases mRNA levels for cytokines, tumor necrosis factor-alpha, interleukin-1alpha, and interleukin-6. Cytokines induce matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA). MMPs and uPA disrupt extracellular matrix. Since matrix damage may play a role in the neuropathological changes seen with TMT toxicity, we determined the effect of TMT on proteolytic enzyme production. Adult rats were injected with 8.0 mg TMT/kg. At different times after TMT injection, tissue samples from frontal lobe and hippocampus were assayed for MMPs and uPA, using gelatin-substrate and casein/plasminogen-substrate zymography. Gelatinase B (92 kDa type IV collagenase) production increased significantly in frontal lobe tissue at 24, 48 and 96 h, and in hippocampus at 48 h compared to saline-injected controls. Gelatinase A (72 kDa type IV collagenase) was significantly decreased at 12 and 24 h in frontal lobe compared to controls. Urokinase-type PA was significantly increased in hippocampus at 12 and 96 h, and in frontal lobe at 96 h compared to controls. Gelatinase B and uPA are up-regulated by TMT in frontal lobe and hippocampus, suggesting that they may contribute to the neuropathology of TMT.
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PMID:Trimethyltin induces gelatinase B and urokinase in rat brain. 921 29

Thirteen coagulation tests evaluating hemostatic and fibrinolytic indices and serum cytokine and plasma endotoxin concentrations were obtained in 34 foals with a positive sepsis score (septic group) and 46 age-matched healthy foals. Compared to healthy foals, the prothrombin, activated partial thromboplastin, and whole blood recalcification times were significantly longer in septic foals. The fibrinogen and fibrin degradation products concentrations, percent plasminogen, alpha-2 antiplasmin, and plasminogen activator inhibitor activities, and tumor necrosis factor and interleukin-6 activities were greater in septic foals. Protein C antigen and antithrombin III activity were significantly lower in septic foals. Blood cultures were positive for growth and endotoxin was detected in 19 of 29 and 15 of 30 septic foals, respectively. In septicemic foals with detectable endotoxin in the plasma, the prothrombin and activated partial thromboplastin times were significantly longer and the plasminogen and antithrombin III activities were significantly less than in septic foals in which endotoxin was not detected. Twenty-three of the 34 septic foals did not survive. Septic foals that did not survive were most likely to have a positive blood culture in which a gram-negative organism was isolated. Histopathologic evidence of hemorrhage was evident in 11 foals at postmortem examination and thrombosis was identified in 2 foals. The prothrombin time was significantly longer in foals that had multisite hemorrhage at postmortem examination. The results of this study indicate that clinically relevant alternations in hemostatic and fibrinolytic indices occur in neonatal foals with septicemia and that derangements can be correlated with the presence of endotoxin in plasma. Derangements in hemostatic or fibrinolytic indices were helpful in identification of septic foals with increased risk of coagulopathy, but were not helpful in predicting hemorrhage as compared to thrombus formation. Survival of septicemic foals was correlated with gram-negative bacteremia, but not with the presence of endotoxin or coagulopathy.
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PMID:Hemostatic and fibrinolytic indices in neonatal foals with presumed septicemia. 950 57

Apoptotic neuronal death is known to occur in the developing brain and in the mature brain of patients with ischemic and degenerative disorders. Although microglial cells are known to become activated in specific conditions, it has not been elucidated whether they enhance or prevent neuronal apoptosis. The present study was intended to observe how microglial cells are involved in neuronal death. When rat primary cortical neurons were incubated with a nitric oxide (NO) donor sodium nitroprusside (SNP; 300 microM) for 10 min, neuronal death occurred 12-16 hr later. The NO-induced neuronal death was inhibited by cycloheximide, and the SNP-treated neurons were characterized by nuclear fragmentation and intact cell membrane under electron microscopy. Agarose gel electrophoresis demonstrated DNA fragmentation of the SNP-treated neurons. Thus, the NO-induced neuronal death appeared to be apoptosis. When neurons were cocultured with rat primary microglial cells, the SNP treatment failed to induce the neuronal death. Because microglia-conditioned medium also prevented apoptotic neuronal death, microglial cells were considered to secrete antiapoptotic factors. The microglia-conditioned medium rescued neurons even when they were added to neuronal cultures after the SNP treatment, implying that the factors acted on neurons in a manner other than scavenging NO. Interleukin-3, interleukin-6, macrophage colony-stimulating factor, and basic fibroblast growth factor, which are known to be secreted by microglial cells, were not effective in preventing NO-induced neuronal death. Among microglia-derived substances, tumor necrosis factor alpha and plasminogen, which are heat-labile proteins, inhibited neuronal apoptosis. The neuroprotective action of the microglia-conditioned medium, however, still remained, even after it was heated. These findings suggest that microglial cells protect neurons against NO-induced lethal damage by secreting heat-labile and heat-stable neuroprotective factors in vitro.
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PMID:Microglial cells prevent nitric oxide-induced neuronal apoptosis in vitro. 971 Feb 61

The avascular cornea has limited access to plasma proteins, including plasminogen, a protein that is synthesized by the liver and supplied to most tissues via the blood. Recent experiments by others using plasminogen-deficient mice revealed the importance of plasmin, the active form of plasminogen, for the maintenance of the normal cornea and for corneal wound healing [Kao, Kao, Bugge, Kaufman, Kombrinck, Converse, Good and Degan (1998) Invest. Ophthalmol. Vis. Sci. 39, 502-508; Drew, Kaufman, Kombrinck, Danton, Daugherty, Degen and Bugge (1998) Blood 91, 1616-1624]. In the present experiments, plasmin was identified as a major serine proteinase in the human cornea. The major plasminogen and plasmin forms on non-reducing zymograms and Western blots had Mr values of 76x10(3) and 85x10(3), with minor forms of Mr 200x10(3), 135x10(3), 68x10(3) and 45x10(3). Angiostatin-like peptides with Mrs of 48x10(3), 45x10(3) and 38x10(3) were observed which bound to lysine-Sepharose and reacted with anti-plasminogen monoclonal antibodies directed towards kringle domains 1-3 of plasminogen. The cornea contained 1.1+/-0.15 microgram of plasminogen+plasmin/cornea, or 0.54+/-0.05 microgram of plasminogen+plasmin/mg of protein. Cornea conditioned medium contained nine times the amount of plasminogen+plasmin that could be extracted from the cornea. These data suggested that corneal cells, unlike most extrahepatic cells, synthesize plasminogen. The synthesis of plasminogen by the cornea was confirmed by immunoprecipitation of metabolically labelled plasminogen, sequencing of its cDNA obtained by reverse transcriptase-PCR and inhibition of protein synthesis. Interleukins-1alpha and -1beta stimulated corneal plasminogen synthesis 2-3-fold; however, interleukin-6 decreased corneal plasminogen synthesis by approx. 40% at early times after addition of the cytokine. By 24 h of culture, no differences were noted in the presence and absence of interleukin-6. Thus the cornea can synthesize plasminogen and regulate its synthesis in response to its environment, including cytokines induced in the cornea by injury and inflammation. Therefore the cornea can control the amount of plasminogen, the precursor of both plasmin and angiostatin.
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PMID:Extrahepatic synthesis of plasminogen in the human cornea is up-regulated by interleukins-1alpha and -1beta. 1021 10

Hyperthyroidism is associated with a higher incidence of arterial thromboembolism; increasing age, atrial fibrillation, and mitral valve abnormalities are risk factors. However, the contribution of endogenous coagulation parameters is unclear. Because thyroid hormone influences receptor and transcription factors, it can be expected that it will influence proteins involved in coagulation processes synthetised in many cells. Fourteen hyperthyroid patients were studied untreated, after 1 week of treatment with propranolol, and after therapeutic treatment with thiamazol. Fourteen matched controls were used for comparison. On each occasion, endothelial marker proteins, coagulation/fibrinolysis factors, and inflammatory (liver) markers were measured. Excess thyroid hormone was associated with elevated levels of most endothelium-associated proteins. In addition, plasma fibronectin and fibrinogen were increased, while plasminogen was decreased. No evidence was found that hyperthyroidism was associated with coagulation/fibrinolysis activation, or with increased levels of the inflammation markers interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) or C-reactive protein (CRP). Propranolol treatment only lowered the von Willebrand factor propeptide, and slightly increased plasminogen. Treatment with thiamazol returned all parameters to normal. Hyperthyroidism increased the plasma levels of most endothelial marker proteins, and of some liver-synthetized proteins. No evidence for coagulation/fibrinolysis activation was found. However, it appears that endothelial activation, which is indicative of a procoagulant state, is present in hyperthyroidism. This may explain the association between hyperthyroidism and thromboembolism especially if other risk factors are present. von Willebrand factor II (vWF:Ag-II) levels may be suitable markers to evaluate acute changes in endothelial function because this parameter responds more rapidly to changes in endothelial function than other factors.
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PMID:Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazol. 1128 84


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