UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Protection against infection with Borrelia burgdorferi is dependent primarily on induction of complement-dependent antibody that can kill the spirochete. Measuring the production of sustained high levels of borreliacidal antibody is thus paramount for determining potential vaccine efficacy. We investigated the borreliacidal antibody response in sera and the amount of antibody produced by cultured lymph node cells of C3H/HeJ mice vaccinated with outer surface protein C (OspC). We showed that recombinant OspC was a weak stimulant of borreliacidal antibody production compared to whole cells of OspC-expressing B. burgdorferi. Mice vaccinated with B. burgdorferi in adjuvant produced a high level (titer, 5,120) of anti-OspC borreliacidal antibody, which waned rapidly. Similarly, borreliacidal antibody production by cultured lymph node cells from vaccinated mice peaked soon after vaccination and then decreased. Treatment of lymph node cells with interleukin-6 (IL-6) augmented borreliacidal antibody production, particularly immunoglobulin G2b, whereas treatment with anti-IL-6 inhibited the borreliacidal response. These findings demonstrate a previously unrecognized role for IL-6 in borreliacidal antibody production that may have important implications for vaccine development.
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PMID:Interleukin-6 enhances production of anti-OspC immunoglobulin G2b borreliacidal antibody. 1140 63

Abnormalities in coagulation and haemostasis represent a well-known link between obesity and thrombosis (both arterial and venous). Several studies have shown that obese patients have higher plasma concentrations of all pro-thrombotic factors (fibrinogen, vonWillebrand factor (vWF), and factor VII), as compared to non-obese controls, with a positive association with central fat. Similarly, plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be higher in obese patients as compared to non-obese controls and to be directly correlated with visceral fat. Furthermore, obesity is characterized by higher plasma concentrations of anti-thrombotic factors, such as tissue-type plasminogen activator (t-PA) and protein C, as compared to non-obese controls, the increase in these factors being likely to represent a protective response partly counteracting the increase in pro-thrombotic factors. The issue of whether adipose tissue contributes directly to plasma PAI-1, its products stimulating other cells to produce PAI-1, or whether it primarily contributes indirectly has not yet been resolved. It has been proposed that the secretion of interleukin-6 (IL-6) by adipose tissue, combined with the actions of adipose tissue-expressed TNF-alpha in obesity, could underlie the association of insulin resistance with endothelial dysfunction, coagulopathy, and coronary heart disease. The role of leptin in impairing haemostasis and promoting thrombosis has been recently reported. Finally, some hormonal abnormalities (androgen, F, catecholamines) associated with the accumulation of body fat may contribute to the impairment of coagulative pathway in obesity. As to intervention strategies, dietary (i.e., low-fat high-fiber diet) and lifestyle (i.e., physical activity) measures have been demonstrated to be effective in improving the obesity-associated pro-thrombotic risk profile.
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PMID:Coagulation and fibrinolysis abnormalities in obesity. 1250 53

In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.
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PMID:Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice. 1260 41

The protein C anticoagulant pathway serves as a major system for controlling thrombosis, limiting inflammatory responses, and potentially decreasing endothelial cell apoptosis in response to inflammatory cytokines and ischemia. The essential components of the pathway involve thrombin, thrombomodulin, the endothelial cell protein C receptor (EPCR), protein C, and protein S. Thrombomodulin binds thrombin, directly inhibiting its clotting and cell activation potential while at the same time augmenting protein C (and thrombin activatable fibrinolysis inhibitor [TAFI]) activation. Furthermore, thrombin bound to thrombomodulin is inactivated by plasma protease inhibitors > 20 times faster than free thrombin, resulting in increased clearance of thrombin from the circulation. The inhibited thrombin rapidly dissociates from thrombomodulin, regenerating the anticoagulant surface. Thrombomodulin also has direct anti-inflammatory activity, minimizing cytokine formation in the endothelium and decreasing leukocyte-endothelial cell adhesion. EPCR augments protein C activation approximately 20-fold in vivo by binding protein C and presenting it to the thrombin-thrombomodulin activation complex. Activated protein C (APC) retains its ability to bind EPCR, and this complex appears to be involved in some of the cellular signaling mechanisms that down-regulate inflammatory cytokine formation (tumor necrosis factor, interleukin-6). Once APC dissociates from EPCR, it binds to protein S on appropriate cell surfaces where it inactivates factors Va and VIIIa, thereby inhibiting further thrombin generation. Clinical studies reveal that deficiencies of protein C lead to microvascular thrombosis (purpura fulminans). During severe sepsis, a combination of protein C consumption, protein S inactivation, and reduction in activity of the activation complex by oxidation, cytokine-mediated down-regulation, and proteolytic release of the activation components sets in motion conditions that would favor an acquired defect in the protein C pathway, which in turn favors microvascular thrombosis, increased leukocyte adhesion, and increased cytokine formation. APC has been shown clinically to protect patients with severe sepsis. Protein C and thrombomodulin are in early stage clinical trials for this disease, and each has distinct potential advantages and disadvantages relative to APC.
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PMID:The protein C pathway. 1297 Jan 21

Drotrecogin alfa (activated) improved survival in patients with severe sepsis in PROWESS, a double-blind, study of 1690 adult patients randomized to drotrecogin alfa (activated) at 24 microg/kg/h (N=850) or placebo (N=840) infused for 96 hours. Pharmacodynamic effects of drotrecogin alfa (activated) were assessed with 15 prospectively defined systemic biomarkers of hemostasis, inflammation and endothelial injury. The last-observation-carried-forward (LOCF) method of imputation for missing observations was the prospectively defined statistical method. The results were also analyzed with only the observed values without imputation for missing data (repeated measures analysis). With both statistical methods, drotrecogin alfa (activated)-treated patients demonstrated antithrombotic (reduced markers of thrombin generation and accelerated normalization of anticoagulant factor, protein C and fibrinolytic factors) and anticoagulant (prolonged PT and APTT) effects compared with placebo. A profibrinolytic (reduction in plasminogen activator inhibitor-1) effect was significant only with the LOCF imputation method in observed case and percent change from baseline analyses. An anti-inflammatory (reduction in interleukin-6) effect was significant only with the LOCF imputation method in change from baseline and percent change from baseline analyses. Drotrecogin alfa (activated) is a new and promising agent for treatment of patients with severe sepsis. The extensive analysis of systemic biomarkers confirms the previously published antithrombotic effects. However, the present results using different statistical methods do not provide a strong basis for systemic anti-inflammatory or pro-fibrinolytic effects. These latter two effects may occur at the local or cellular level. The systemic biomarkers reported here might not be the most appropriate approach to demonstrate these potential effects of drotrecogin alfa (activated).
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PMID:Drotrecogin alfa (activated) (recombinant human activated protein C) reduces host coagulopathy response in patients with severe sepsis. 1511 70

The effects of n-acetyl cysteine (NAC), s-allyl cysteine (SAC), s-ethyl cysteine, s-methyl cysteine and s-propyl cysteine (SPC) activity on Balb/cA mice against diabetic complications were examined. These complications included hyperglycemia, hyperlipidemia, oxidation stress, blood coagulation, and cytokine imbalance. To induce diabetes, mice were treated with streptozotocin i.p. for 5 consecutive days. Five cysteine-containing compounds at 1 g/L were added to the drinking water. After intake of the 5 cysteine-containing agents for 4 wk, body weight loss, plasma concentrations of glucose and insulin, and fibronectin levels were improved (P < 0.05) in diabetic mice. The administration of these agents restored the glutathione level (P < 0.05), reduced the loss of catalase and glutathione peroxidase activities in kidney and liver (P < 0.05), and decreased glucose-induced lipid oxidation, as assessed by malondialdehyde formation (P < 0.05). In all diabetic mice, the intake of these agents reduced triglyceride levels in plasma and liver (P < 0.05); however, only NAC, SAC and SPC treatments reduced cholesterol level in liver (P < 0.05). These cysteine-containing agents elevated the activity of 2 fibrinolytic factors, protein C and antithrombin III (P < 0.05). The overexpression of interleukin-6 and tumor necrosis factor-alpha in diabetic mice was suppressed by the intake of the 5 cysteine-containing agents (P < 0.05). Via their antioxidant activities, the 5 compounds effectively improved glycemic control, delayed oxidation damage, downregulated inflammatory cytokines, and enhanced anticoagulant activity in diabetic mice. These data support the multiple roles of these agents as potential protective agents for delaying diabetic deterioration.
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PMID:Five cysteine-containing compounds delay diabetic deterioration in Balb/cA mice. 1557 20

The principles of Virchov's triad appear to be operational in atherothrombosis or arterial thrombosis: local flow changes and particularly vacular wall damage are the main pathophysiological elements. Furthermore, alterations in arterial blood composition are also involved although the specific role and importance of blood coagulation is an ongoing matter of debate. In this review we provide support for the hypothesis that activated blood coagulation is an essential determinant of the risk of atherothrombotic complications. We distinguish two phases in atherosclerosis: In the first phase, atherosclerosis develops under influence of "classical" risk factors, i.e. both genetic and acquired forces. While fibrinogen/fibrin molecules participate in early plaque lesions, increased activity of systemic coagulation is of no major influence on the risk of arterial thrombosis, except in rare cases where a number of specific procoagulant forces collide. Despite the presence of tissue factor - factor VII complex it is unlikely that all fibrin in the atherosclerotic plaque is the direct result from local clotting activity. The dominant effect of coagulation in this phase is anticoagulant, i.e. thrombin enhances protein C activation through its binding to endothelial thrombomodulin.The second phase is characterized by advancing atherosclerosis, with greater impact of inflammation as indicated by an elevated level of plasma C-reactive protein, the result of increased production influenced by interleukin-6. Inflammation overwhelms protective anticoagulant forces, which in itself may have become less efficient due to down regulation of thrombomodulin and endothelial cell protein C receptor (EPCR) expression. In this phase, the inflammatory drive leads to recurrent induction of tissue factor and assembly of catalytic complexes on aggregated cells and on microparticles, maintaining a certain level of thrombin production and fibrin formation. In advanced atherosclerosis systemic and vascular wall driven coagulation becomes more important and elevated levels of D-dimer fragments should be interpreted as markers of this hypercoagulability.
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PMID:Blood coagulation and the risk of atherothrombosis: a complex relationship. 1557 98

Larger numbers of pneumococci were detected in the nasal tract compared to the lung, cervical lymph nodes, and spleen 1, 2, 4, 7, 14, and 21 days after nasal challenge with Streptococcus pneumoniae strain EF3030. In this mouse model of pneumococcal carriage, peripheral S. pneumoniae pneumococcal surface adhesin A (PsaA)-specific humoral responses (immunoglobulin G2a [IgG2a] >> IgG1 = IgG2b > IgG3) were significantly higher than pneumococcal surface protein A (PspA)-specific, genetic toxoid derivative of pneumolysin (PdB)-specific, or pneumococcal surface protein C (PspC)-specific serum antibody levels. However, PspA-specific mucosal IgA antibody levels were significantly higher than those against PsaA, PdB, and PspC. In general, both PsaA- and PspA-specific lung-, cervical lymph node-, nasal tract-, and spleen-derived CD4(+) T-cell cytokine (interleukin-4, interleukin-6, granulocyte-macrophage colony-stimulating factor, gamma interferon, and tumor necrosis factor alpha) and proliferative responses were higher than those for either PspC or PdB. Taken together, these findings suggest that PsaA- and PspA-specific mucosal responses as well as systemic humoral and T helper cell cytokine responses are predominantly yet differentially induced during pneumococcal carriage.
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PMID:Differential PsaA-, PspA-, PspC-, and PdB-specific immune responses in a mouse model of pneumococcal carriage. 1566 44

Genetic studies in familial lung fibrosis have demonstrated an association with surfactant protein C genes: two mutations have been found resulting in protein misfolding and causing type-II epithelial cell injury. Remarkably, different histological patterns were observed in the affected subjects, suggesting the influence of modifier genes and/or environmental factors. Surfactant protein C gene variations have not, however, been associated with sporadic cases, i.e. idiopathic pulmonary fibrosis (IPF). Susceptibility to IPF probably involves a combination of polymorphisms related to epithelial cell injury and abnormal wound healing. To date, the genetic associations with IPF that have been reported in different cohorts include the genes encoding tumour necrosis factor (TNF; -308 adenine), interleukin-1 receptor antagonist (+2018 thymidine) and association with severity and progression (interleukin-6/TNF receptor II and transforming growth factor-beta1 (TGFB1; +869 cytosine)), but none of these associations have been replicated by others. Unlike in IPF, immunological inflammation seems to be more prominent in the pathogenesis of scleroderma lung fibrosis, being an autoimmune disease with specific autoantibodies, such as antitopoisomerase antibodies, in patients with diffuse lung disease, and anticentromere antibodies, in patients with pulmonary vascular disease. Antitopoisomerase antibody positivity is associated with the carriage of human leukocyte antigen DRB1*11 and DPB1*1301 alleles, suggesting the recognition of a specific amino-acid motif. Extended haplotype analysis also supports the conclusion that TNF may be the primary association with anticentromere positivity. Intriguingly, associations with TGFB1 and genes involved in extracellular matrix homeostasis have been reported in this disease. In conclusion, significant steps forward have been taken in the understanding of the genetic contribution to fibrosing lung diseases, but major challenges lay ahead. It is the present authors' opinion that only a combined approach studying large numbers of familial and sporadic cases, all clinically well phenotyped, using multiple distinct cohorts, and genotyped according to relevant gene ontologies will be successful. It will be necessary to be particularly vigilant with regard to phenotype; the absence of very strong reproducible associations may be because of the rigidity of phenotype definition, coupled with the possibility that idiopathic pulmonary fibrosis may still be a heterogeneous group of diseases, despite the more rigid definition set out by the European Respiratory Society/American Thoracic Society statement.
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PMID:Genetics of fibrosing lung diseases. 1586 52

Pentoxifylline (PTX, a methylxanthine derivative) has been found to interrupt early gene activation for tumour necrosis factor, interleukin-1, interleukin-6 and tissue factor production and to improve survival from experimental sepsis. During endotoxaemia, lipopolysaccharide (LPS, endotoxin) and proinflammatory cytokines trigger the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation. The present study was undertaken to determine whether pentoxifylline could prevent coagulation disturbances in LPS-treated rabbits. Endotoxaemia was induced with E. coli lipopolysaccharide in New Zealand White rabbits. Forty rabbits were used and divided into four equal groups. Group 1 served as a control group; Group 2: lipopolysaccharide was injected intravenously, Group 3: pentoxifylline was injected intraperitoneally, Group 4: lipopolysaccharide and pentoxifylline were injected simultaneously. Blood samples were collected 6 h after the treatments. In rabbits with endotoxin-induced DIC, platelet count, leukocyte count, percentage of differential leukocyte values, fibrinogen level, antithrombin III (AT-III) and protein C (PC) activity were decreased. Moreover, activated partial thromboplastin time (APTT) and prothrombin time (PT) were prolonged when compared to the control group. In conclusion, haemostatic disturbances associated with endotoxin-induced DIC were moderately suppressed by the administration of PTX.
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PMID:Effect of pentoxifylline on endotoxin-induced haemostatic disturbances in rabbits. 1615 28

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