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)

Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine synthesized by several cell types, e.g., inflammatory cells, such as monocytes, and resident renal cells, such as human tubular epithelial cells (TECs). Besides induction of monocyte recruitment, MCP-1 has been suggested to induce non-leukocytes to produce cytokines and adhesion molecules. Inflammation of the tubulointerstitium is a hallmark of many renal diseases and contributes to progression of renal failure; the purpose therefore of this study was to investigate the influence of MCP-1 on markers of inflammatory activation in human TECs. MCP-1 stimulated interleukin-6 (IL-6) secretion and intercellular adhesion molecule-1 (ICAM-1) synthesis in a time- and dose-dependent manner. In parallel, MCP-1 increased IL-6 and ICAM-1 mRNA expression in human TECs. Pretreatment with pertussis toxin, GF109203X, BAPTA-AM, and pyrrolidine dithiocarbamate inhibited MCP-1-dependent IL-6 and ICAM-1 synthesis, suggesting the involvement of Gi-proteins, protein kinase C, intracellular Ca(2+), and nuclear factor-kappaB (NF-kappaB) in MCP-1 signaling. Using electrophoretic gel mobility shift assay, we observed that MCP-1 stimulated binding activity of NF-kappaB. Binding activity of the activator protein-1 (AP-1), which has been implicated to regulate induction of the IL-6 gene together with NF-kappaB, was also stimulated by MCP-1. In the present experiments, NF-kappaB and AP-1 were involved in the MCP-1-mediated induction of IL-6, as demonstrated by cis element double-stranded (decoy) oligonucleotides (ODN). In contrast to IL-6 release, MCP-1-induced ICAM-1 expression was predominantly dependent on NF-kappaB activation. These results document for the first time that MCP-1 induces an inflammatory response in human TECs. This may be an important new mechanism in the pathogenesis of tubulointerstitial inflammation.
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PMID:MCP-1 induces inflammatory activation of human tubular epithelial cells: involvement of the transcription factors, nuclear factor-kappaB and activating protein-1. 1203 83

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal expansion of malignant plasma cells within the bone marrow. It accounts for 10% of all haematological malignant diseases and 1% of all malignancies. The median age of patients at the time of the diagnosis is 70 years. The characteristic clinical features of MM are bone marrow failure, susceptibility to infections, bone pain, pathological bone fractures, hypercalcaemia, and renal failure. Though MM is currently incurable, the important progress in chemotherapy has resulted in an improvement in survival from a median of 7 months in the 1950-ies to about 3 years today. Advances in the diagnosis and in supportive treatment of infections, hypercalcaemia, and renal failure also contributed to the prolongation of survival. For decades, the gold standard of treatment had been oral melphalan alone or in combination with prednisolone. Combination chemotherapy has not improved overall survival (OS), but these regimens have led to the prolongation of event-free survival (EFS) and also to a better quality of life. High-dose chemotherapy with haemopoietic stem cell rescue resulted in a great improvement in EFS as well as OS. For those very few who have an HLA-compatible donor and are under 55, allogeneic bone marrow transplantation offers the best hope of survival but comes at a greatly increased risk of toxicity. There are conflicting data in the literature concerning the role of interferon-alpha; it seems to be able to prolong the duration of the plateau phase. Current treatment is moving towards an approach using sequential therapy. This involves induction therapy proceeding to high-dose chemotherapy with some form of stem-cell rescue. Bisphosphonates reduce hypercalcaemia, bone pain and can inhibit bone destruction. They also possess a direct antitumor activity. The better understanding of the pathomechanism of the disease gives the opportunity of the application of new therapeutic modalities such as antagonising the effect of interleukin-6 (IL-6), or idiotypic vaccination.
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PMID:[Therapy of multiple myeloma] 1205 Jul 24

Angiotensin II (Ang II), the most important component of the renin-angiotensin system, is usually associated with hypertension and renal failure. Through its pro-inflammatory actions, it also plays an important role in each step of the development of atherosclerotic plaques and plaque rupture. Ang II stimulates the expression of nuclear factor-kappaB (NFkappaB), a transcription factor which regulates gene expression of inflammatory cytokines such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1). Ang II type 1 receptors (AT1) and angiotensin converting enzyme (ACE) are dramatically increased in atherosclerotic plaques, particularly in monocytes at the fibrous cap. Thus, in multiple ways, Ang II is a critical factor in atherosclerotic plaque formation, inflammation and plaque stability. ACE inhibitors and AT1R inhibitors could therefore be appropriate therapeutic agents in the treatment of atherosclerosis.
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PMID:Angiotensin II as a pro-inflammatory mediator. 1209 Jul 26

Transgenic mice carrying human IL-6 cDNA fused with a murine major histocompatibility class-I promoter (H-2L(d)) were serially administered with anti-interleukin-6 receptor (IL-6R) monoclonal antibody (mAb), MR16-1, from the age of 4 weeks to estimate its efficacy on a variety of disorders developed in these mice, most of which are similar to the disorders associated with Castleman's disease. In the control mice treated with isotype-matched mAb, a massive and multiple IgG1 plasmacytosis, mesangial proliferative glomerulonephritis, leukocytosis, thrombocytosis, anemia and abnormalities of blood chemical parameters have developed in accordance with the elevation of serum IL-6, and 50% of mice have died of renal failure by 18 weeks of age. In contrast, the treatment with MR16-1 prevented all these symptoms and prolonged the lifetime of the majority of the mice. Thus, the constitutive overexpression of IL-6 caused various disorders, and the treatment with anti-IL-6R mAb completely prevented from these symptoms. These results clearly confirm that IL-6 indeed plays an essential role in the pathogenesis of a variety of disorders. Furthermore, anti-IL-6R mAb could provide novel therapy for Castleman's disease and MR16-1 should be a useful tool to estimate therapeutic potential of IL-6 antagonists in a variety of murine models for human disease.
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PMID:Anti-interleukin 6 (IL-6) receptor antibody suppresses Castleman's disease like symptoms emerged in IL-6 transgenic mice. 1263 73

Blockade of tissue factor before lethal sepsis prevents acute lung injury and renal failure in baboons, indicating that activation of coagulation by tissue factor is an early event in the pathogenesis of acute lung injury and organ dysfunction. We hypothesized that blockade of tissue factor would also attenuate these injuries in established sepsis by prevention of further fibrin deposition and inflammation. Twelve male baboons received heat-killed Escherichia coli intravenously followed 12 hours later by live E. coli infusion. Six animals were treated 2 hours after the live bacteria with site-inactivated Factor VIIa, a competitive tissue factor inhibitor, and six animals were vehicle-treated sepsis control subjects. Animals were ventilated and monitored for 48 hours. Physiologic and hematologic parameters were measured every 6 hours, and pathologic evaluation was performed after 48 hours. Animals treated with site inactivated Factor VIIa had less severe lung injury, with preserved gas exchange, better lung compliance and histology scores, and decreased lung wet/dry weight. In treated animals, urine output was higher, metabolic acidosis was attenuated, and renal tubular architecture was protected. Coagulopathy was attenuated, and plasma interleukin-6, interleukin-8, and soluble tumor necrosis factor receptor-1 levels were significantly lower in the treated animals. These results show that blockade of coagulation attenuates acute lung and renal injury in established Gram-negative sepsis accompanied by antiinflammatory effects of therapy.
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PMID:Blockade of tissue factor: treatment for organ injury in established sepsis. 1271 43

Vitamin E supplementation could elevate circulating vitamin E metabolites while modulating oxidative and inflammatory status in end-stage renal failure patients undergoing hemodialysis. Plasma concentrations of carboxyethyl-hydroxychromanols (alpha- and gamma-CEHC), ascorbic acid, alpha- and gamma-tocopherols, F2-isoprostanes, and inflammatory biomarkers [tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), ferritin, and C-reactive protein (CRP)] were measured in blood samples obtained from patients (n = 11) before and after dialysis on two occasions prior to, and at 1 and 2 mon of daily vitamin E supplementation (400 IU RRR-alpha-tocopherol). Supplementation nearly doubled plasma alpha-tocopherol concentrations (from 18 +/- 0.5 to 31 +/- 1.7 microM, P < 0.0001), whereas gamma-tocopherol concentrations decreased (from 2.8 +/- 0.3 to 1.7 +/- 0.2 microM, P = 0.001). Serum alpha-CEHC increased 10-fold from 68 +/- 3 to 771 +/- 175 nM (P < 0.0001), and gamma-CEHC increased from 837 +/- 164 to 1136 +/- 230 nM (P = 0.008). Vitamin E supplementation also increased postdialysis hematocrits from 38 +/- 1% to 41 +/- 1% (P < 0.001). Dietary antioxidant intakes (vitamins E and C) were low in most subjects; plasma ascorbic acid levels (88 +/- 27 microM) decreased significantly with dialysis (33 +/- 11 microM, P = 0.01). Plasma IL-6, CRP, TNF-alpha, and free F2-isoprostane concentrations were elevated throughout the study. There is a complex relationship between chronic inflammation and oxidative stress that is not mitigated by short-term vitamin E supplementation. Importantly, serum vitamin E metabolite concentrations that increased 10-fold within 30 d of supplementation did not increase further, suggesting routes other than urine for removal of metabolites.
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PMID:Vitamin E supplementation increases circulating vitamin E metabolites tenfold in end-stage renal disease patients. 1457 59

Protein-energy malnutrition (PEM) and inflammation are common in patients with chronic kidney disease (CKD) and worsen as the CKD progresses toward the end-stage renal disease (ESRD). These conditions are major predictors of poor clinical outcome in kidney failure, as reflected by a strong association between hypoalbuminemia and cardiovascular disease (CVD). It has been suggested that inflammation is the cause of both PEM and CVD and, hence, the main link among these conditions, but these hypotheses are not well established. Increased release or activation of inflammatory cytokines, such as interleukin-6 or tumor necrosis factor alpha, may suppress appetite, cause muscle proteolysis and hypoalbuminemia, and may be involved in atherogenesis. Increasing serum levels of proinflammatory cytokines caused by reduced renal function, volume overload, oxidative or carbonyl stress, decreased levels of antioxidants, increased susceptibility to infection in uremia, and the presence of comorbid conditions may lead to inflammation in CKD patients. In hemodialysis patients, the exposure to dialysis tubing and dialysis membranes, poor quality of dialysis water, back-filtration or back-diffusion of contaminants, and foreign bodies in dialysis access maybe additional causes of inflammation. Similarly, episodes of overt or latent peritonitis, peritoneal dialysis (PD) catheter and its related infections, and constant exposure to PD solution may contribute to inflammation in these patients. The degree to which PEM in dialysis patients is caused by inflammation is not clear. Because both PEM and inflammation are strongly associated with each other and can change many nutritional measures and outcome concurrently in the same direction, the terms malnutrition-inflammation complex syndrome (MICS) and/or malnutrition-inflammation-atherosclerosis (MIA) have been suggested to denote the important contribution of both of these conditions to poor clinical outcome. Maintenance dialysis patients who are underweight or who have low serum levels of cholesterol, creatinine, or homocysteine may be suffering from the MICS/MIA and its subsequent poor outcome. Consequently, obesity and hypercholesterolemia may appear protective, which is known as reverse epidemiology. Although MICS/MIA may have a significant contribution in reversing the traditional CVD risk factors in dialysis patients, it is not clear whether PEM or inflammation and their complications can be effectively managed in CKD and ESRD or whether their management improves clinical outcome.
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PMID:Inflammation and nutrition in renal insufficiency. 1470 70

Cardiovascular disease is common in patients with chronic kidney disease (CKD). As renal function fails, many patients become progressively malnourished, as evidenced by reduced levels of albumin, prealbumin, and transferrin. Malnourished patients have increased levels of C reactive protein (CRP), interleukin-6 (IL-6), and concomitant cardiovascular disease when they reach end stage. Many diseases that cause CKD, diabetes, and hypertension are also associated with cardiovascular disease. Thus the direct effect of renal failure per se directly contributing to the inflammation-malnutrition-atherosclerosis paradigm is not completely established in early stages of CKD. Some aspects of progressive renal failure, however, cause changes in plasma composition and endothelial structure and function that favor vascular injury. As renal function fails, hepatic apo A-I synthesis decreases and HDL levels fall. HDL is an important antioxidant and defends the endothelium from the effects of cytokines. Inflammation causes further structural and functional abnormalities in HDL. Apolipoprotein C III (apo C III), a competitive inhibitor of lipoprotein lipase is increased in CKD. Serum triglyceride levels increase as a result of accumulation of intermediate-density lipoprotein (IDL) comprising VLDL and chylomicron remnants. These impede vascular relaxation and are associated with cardiovascular disease. Activation of the renin angiotensin axis is a component of many renal diseases and adaptation to loss of renal mass. Angiotensin II (AngII) activates NADPH oxidases, leading to production of the superoxide anion and decreased availability of nitric oxide (NO), further impairing vascular function. H(2)O(2), produced as a consequence of superoxide dismutation, stimulates vascular cell proliferation and hypertrophy. Leukocyte-derived myeloperoxidase functions as an "NO Oxidase" in the inflamed vasculature and contributes to decreased NO bioavailability and compromised vascular reactivity. The changes in lipoprotein composition and structure as well as AngII-mediated alterations in endothelial function amplify the effect of subsequent inflammatory events.
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PMID:The role of oxidative stress-altered lipoprotein structure and function and microinflammation on cardiovascular risk in patients with minor renal dysfunction. 1497 55

Patients with cirrhosis and ascites show systemic and splanchnic arterial vasodilation, which causes a reduction in effective arterial blood volume and the activation of hormonal anti-natriuretic systems. Renal impairment is the most important predictor of hospital mortality in cirrhotic patients with SBP. In patients with SBP, the inflammatory response to the infection (TNF-alpha, IL-6) may be an important mechanism of renal dysfunction. Ascitic-fluid NO metabolites are related independently to the development of renal impairment. Treatment of SBP with intravenous albumin in addition to cefotaxime prevents renal impairment and reduces mortality in comparison with treatment with cefotaxime alone. As soon as ascites develops, liver transplantation should be considered in eligible patients, especially when local mean waiting times exceed life expectancy. Nitric oxide (NO), tumour necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) have been implicated in the pathogenesis of circulatory alterations observed in cirrhotic patients with ascites. Kidney failure is one of the main factors associated with mortality in patients with end-stage liver disease developing complications, particularly severe infections and variceal haemorrhage. Renal impairment occurs in patients with the highest concentration of cytokines in plasma and ascitic fluid and is associated with marked activation of the renin-angiotensin system. In patients with spontaneous bacterial peritonitis (SBP), serum and ascitic fluid levels of NO metabolites (nitrites and nitrates) were higher than those of patients with sterile ascites, and renal impairment is considered to be caused by a decrease in effective arterial blood volume as a result of the infection. The administration of albumin prevents deterioration of renal function and reduces mortality in these patients. However, SBP and renal dysfunction are late complications in the course of liver cirrhosis. As soon as ascites develops, liver transplantation should be considered in eligible patients, especially when local mean waiting times exceed life expectancy. A better knowledge of metabolic disorders associated with the early stage of cirrhosis is essential for the development of optimal therapeutic strategies for the prophylaxis and treatment of portal hypertension and its complications.
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PMID:Nitric oxide and renal function in cirrhotic patients with ascites: from physiopathology to practice. 1516 58

The advanced glycation end products (AGEs) are a heterogeneous class of molecules, including the following main subgroups: bis(lysyl)imidazolium cross-links, hydroimidazolones, 3-deoxyglucosone derivatives, and monolysyl adducts. AGEs are increased in diabetes, renal failure, and aging. Microvascular lesions correlate with the accumulation of AGEs, as demonstrated in diabetic retinopathy or renal glomerulosclerosis. On endothelial cells, ligation of receptor for AGE (RAGE) by AGEs induces the expression of cell adhesion molecules, tissue factor, cytokines such as interleukin-6, and monocyte chemoattractant protein-1. A chief means by which AGEs via RAGE exert their effects is by generation of reactive oxygen species, at least in part via stimulation of NADPH oxidase. Diabetes-associated vascular dysfunction in vivo can be prevented by blockade of RAGE. Thus, agents that limit AGE formation, increase the catabolism of these species, or antagonize their binding to RAGE may provide new targets for vascular protection in diabetes.
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PMID:Protein glycation: a firm link to endothelial cell dysfunction. 1529 85


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