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)

Tumor necrosis factor (TNF) has cytotoxic and gene-inductive activities on several cell types. Previous studies on L929 fibrosarcoma cells have revealed that the mitochondrial electron transport system plays a key role in inducing TNF cytotoxicity, presumably by the formation of reactive oxygen intermediates (ROI). Here we report that mitochondria-derived intermediates are not only cytotoxic but, in addition, function as signal transducers of TNF-induced gene expression. The activation of NF kappa B, which fulfills an important role in TNF-induced gene transcription, could be blocked by interference with the mitochondrial electron transport system. Furthermore, antimycin A, a mitochondrial inhibitor that increases the generation of ROI, potentiated TNF-triggered NF kappa B activation. The dual role of mitochondria-derived intermediates in cytotoxicity and immediate-early gene induction of TNF was further substantiated by isolating L929 subclones which lacked a functional respiratory chain. This depletion of the mitochondrial oxidative metabolism resulted in resistance towards TNF cytotoxicity, as well as in inhibition of NF kappa B activation and interleukin-6 gene induction by TNF. These findings suggest that mitochondria are the source of second messenger molecules and serve as common mediators of the TNF-cytotoxic and gene-regulatory signaling pathways.
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PMID:Depletion of the mitochondrial electron transport abrogates the cytotoxic and gene-inductive effects of TNF. 834 50

Cardiac operations with cardiopulmonary bypass cause a systemic inflammatory response, which can lead to organ injury and postoperative morbidity. Causative factors include surgical trauma, contact of blood with the extracorporeal circuit, and lung reperfusion injury on discontinuing bypass. Advances in immunological techniques have allowed measurement of both plasma and intracellular components of this multifaceted perioperative response. This includes activation of the complement, coagulation, fibrinolytic, and kallikrein cascades, activation of neutrophils with degranulation and protease enzyme release, oxygen radical production, and the synthesis of various cytokines from mononuclear cells (including tumor necrosis factor, interleukin-1, and interleukin-6). Advances in our understanding of the interactions between these markers of cellular and humoral responses to cardiopulmonary bypass will enable more effective intervention to reduce the deleterious effects and improve the outlook for patients undergoing cardiac operations beyond the 1990s.
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PMID:Inflammatory response to cardiopulmonary bypass. 797 13

Liposome-encapsulated hemoglobin (LEH) has been tested in animals as an oxygen-carrying red cell substitute and has been shown to be beneficial in the treatment of hemorrhagic shock. The effects of LEH on immune responses have not been studied thoroughly in any well-controlled model. Using a murine model, we evaluated nephrotoxicity and hepatotoxicity as well as immune function parameters following LEH administration. Following intravenous administration of LEH, 1) a serum spike of interleukin-6 (IL-6) occurred in mice at 4-8 hours, with no elevation of IL-1, tumor necrosis factor (TNF), or interferon-gamma (IFN-gamma); 2) the serum liver function enzymes SGOT (AST, aspartate aminotransferase) and SGPT (ALT, alanine aminotransferase) were elevated at 48 hours; 3) only a slight increase in serum antibody to bovine hemoglobin was observed; and 4) increased hematopoietic activity was observed in the spleen and bone marrow. The finding that only IL-6 but not the associated TNF, IL-1, or IFN-gamma is secreted in vivo following LEH administration is novel and may have significance in defining the mechanisms underlying specific adverse responses observed with LEH administration in animals.
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PMID:Multiple responses to administration of liposome-encapsulated hemoglobin (LEH): Effects on hematopoiesis and serum IL-6 levels. 859 72

A 71-year-old woman remained under the rubble of her house for 4 hours after an accidental gas explosion. She suffered from a crush syndrome associating fractures, minor skin burns (< 10% body surface area), inhalation lung injury and moderate hypothermia (34 degrees C). In addition to local signs of compression of the lower limbs, the patient presented with hypovolemic shock and developed acute renal failure on day 3. We describe here the variations in hemodynamic and oxymetric parameters and cytokine response during the first post-injury week. A vasoplegic state resulting from low systemic vascular resistances with progressively increasing cardiac index, oxygen delivery and oxygen consumption closely followed the brief hypovolemic shock. Tumor necrosis factor-alpha remained below normal levels while interleukin-6 increased markedly with a major peak on day 2, in parallel with the drop in systemic vascular resistances. Interleukin-6 is a mediator of impairment in cell membrane function and a vasoconstriction inhibitor. Isolated increased interleukin-6 has been previously reported in severely burned patients suggesting a pathophysiological and hemodynamic similarity between crush syndrome and burn injury.
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PMID:[Hemodynamic profile and serum cytokines in crush syndrome. Analogy with severe burns]. 868 94

Induction of hepatic nitric oxide synthase (NOS) by tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 beta), interferon-gamma (IFN gamma), interleukin-6 (IL-6), and lipopolysaccharide was assessed as activity and immunoreactive protein. Hepatic NOS activity was cytosolic and had cofactor requirements consistent with inducible nitric oxide synthase (NOS2). NOS induction by TNF alpha was dose dependent from concentrations of 0.06 to 60 nM and was increased 2-3-fold by IFN gamma. NOS induction was reflective of total TNF alpha binding to hepatocyte receptors. Hepatocyte TNF alpha binding fit a biphasic curve with high affinity (K(d) = 1.4 nM, Bmax = 3157 sites) and low affinity (K(d) = 157 nM, Bmax = 204,948 sites) elements. NOS2 activity was induced by lipopolysaccharide, IL-1 beta, TNF alpha, and IFN gamma but not by IL-6. All cytokine stimuli were inhibited by antioxidants. Oxygen radical generation was directly measured as dichlorofluoroscein fluorescence in isolated mitochondria. Mitochondria from TNF alpha-treated hepatocytes generated more oxygen radicals than did controls. Antioxidants reduced mitochondrial generation of oxygen radicals. Activation of the transcription factor nuclear factor-kappa B by TNF alpha, IFN gamma, and IL-1 beta was assessed by gel shift analysis. Cytokine treatment increased nuclear factor-kappa B binding, and the addition of antioxidants or rotenone inhibited cytokine activation. Taken together, these data suggest that oxygen radicals, possibly generated by mitochondria, play a major role in NOS2 induction by cytokines.
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PMID:Characterization of hepatic nitric oxide synthase: identification as the cytokine-inducible form primarily regulated by oxidants. 870 Jan 34

Leukocyte depletion during cardiopulmonary bypass has been demonstrated in animal experiments to improve pulmonary function. Conflicting results have been reported, however, with clinical depletion by arterial line filter of leukocytes at the beginning of cardiopulmonary bypass. In this study, we examined whether leukocyte depletion from the residual heart-lung machine blood at the end of cardiopulmonary bypass would improve lung function and reduce the postoperative inflammatory response. Thirty patients undergoing elective heart operations were randomly allocated to a leukocyte-depletion group or a control group. In the leukocyte-depletion group (n = 20), all residual blood (1.2 to 2.1 L) was filtered by leukocyte-removal filters and reinfused after cardiopulmonary bypass, whereas in the control group an identical amount of residual blood after cardiopulmonary bypass was reinfused without filtration (n = 10). Leukocyte depletion removed more than 97% of leukocytes from the retransfused blood (p < 0.01) and significantly reduced circulating leukocytes (p < 0.05) and granulocytes (p < 0.05) compared with the control group. Levels of the inflammatory mediator thromboxane B2 determined at the end of operation (p < 0.05) were significantly lower in the depletion group than in the control group, whereas no statistical differences in interleukin-6 levels were found between the two groups. After operation, pulmonary gas exchange function (arterial oxygen tension at a fraction of inspired oxygen of 0.4) was significantly higher in the leukocyte-depletion group 1 hour after arrival to the intensive care unit (p < 0.05) and after extubation (p < 0.05). There were no statistical differences between the two groups with respect to postoperative circulating platelet levels and blood loss, and no infections were observed during the whole period of hospitalization. These results suggest that leukocyte depletion of the residual heart-lung machine blood improves postoperative lung gas exchange function and is safe for patients who are expected to have a severe inflammatory response after heart operations.
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PMID:Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. 875 18

Effects on the immune system of 6-min "all-out" ergometer rowing were investigated over 2 days (2 x 3 bouts) in eight male oarsmen with a maximal oxygen uptake of 5.5 +/- 0.1 l/min (mean +/- SE). Blood samples were obtained before, during, and 2 h after each bout and on the day after the last bout. Compared with levels at rest, the first bout of exercise increased the concentration of leukocytes (2-fold); neutrophilic granulocytes (2-fold); lymphocytes (2-fold); monocytes (2-fold); the blood mononuclear cell (BMNC) subsets CD3+ (2-fold), CD4+ (2-fold), CD8+ (3-fold), CD16+ (8-fold), CD19+ (2-fold), and CD14+ (2-fold); the NK cell activity (2-fold); and plasma interleukin-6 (3-fold) (P < 0.05). During the last bout even higher levels were noted for leukocytes (3-fold); neutrophilic granulocytes (3-fold); lymphocytes (4-fold); the BMNC subsets CD4+ (3-fold), CD8+ (5-fold), CD16+ (13-fold), CD19+ (5-fold), and CD14+ (3-fold); and for the NK cell activity (4-fold) (P < 0.05). During the recovery periods all values were at or above the level at rest, and elevated concentrations of leukocytes (38%), neutrophilic granulocytes (48%), and lymphocytes (46%) reflected in the BMNC subsets and increased NK cell activity (119%) were also noted on the day after the last bout (P < 0.05). The results show that maximal exercise with large muscle groups provokes higher immune responses during repetitive bouts.
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PMID:Lymphocytes and NK cell activity during repeated bouts of maximal exercise. 876 Feb 24

Necrotizing enterocolitis (NEC) is a neonatal disorder of unknown cause characterized by rapid necrosis of the bowel, primarily the ileum and colon. It is a worldwide problem. NEC is the most common gastrointestinal emergency in the neonatal intensive care unit, and ranks second as a cause of neonatal death. The incidence of NEC is inversely proportional to the birth weight and the degree of maturity. Infants born at or before 28 weeks gestational age have not received 80 per cent of the magnesium and 67 per cent of the copper found at term. Congenital deficiencies of these essential minerals may be compounded by high renal or gastrointestinal losses and high metabolic demand during the preterm infant's accelerated growth. Platelet thrombi appear early in the intestinal microvasculature in NEC. Platelet thrombosis and release of vasoconstrictor, platelet aggregating thromboxane A2 (TXA2) in human NEC appears to potentiate the intestinal ischaemia and necrosis in neonates who develop NEC. Magnesium and copper deficiency each enhance the synthesis of TXA2. Plasma levels of the inflammatory cytokines tumour necrosis factor (TNF) and interleukin-6 (IL-6) are increased in NEC and in magnesium deficiency; these experimentally produce shock and tissue injury, especially of the intestine. The synthesis of the potent vasoconstrictor endothelin is increased in magnesium deficiency. NEC has been regarded as a luminal insult that causes local generation of destructive oxygen free radicals. Tissues from animals deficient in magnesium are more susceptible to oxidative injury and lipid peroxidation than tissues from normal animals. Magnesium and copper deficiency impair antioxidant defence through decreased synthesis of glutathione and reduced activity of Cu/Zn superoxide dismutase, respectively. Although the aetiology of NEC is unknown, there appears to be sufficient data to implicate magnesium and possibly copper deficiencies in the pathogenesis. Consequences of deficiency of one or both minerals may include increased synthesis or activity of injurious mediators: IL-1, IL-6, TNF, TXA2, endothelin, and oxygen free radicals. A prospective trial of magnesium supplementation, but not copper supplementation, in very premature neonates can be recommended, with NEC as one of the outcome measures.
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PMID:A review of evidence for a role of magnesium and possibly copper deficiency in necrotizing enterocolitis. 881 95

The endothelial cell response to hypoxia involves a range of adaptive mechanisms that reflect an active response of the cell's biosynthetic and metabolic apparatus. Hypoxia-mediated suppression of endothelial barrier function, resulting in increased vascular leakage, is likely to contribute to pulmonary and cerebral edema associated with high altitude and is closely associated with a fall in intracellular cyclic AMP levels. Buttressing of this second messenger pathway in the endothelium using membrane permeant cyclic AMP analogs prevents increased vascular leakage due to hypoxia. Application of this principle to organ preservation has shown that supplementation with cyclic AMP analogs or inhibition of endogenous cAMP metabolism enables extension of the time a harvested organ can remain extracorporeally, after which transplantation is successful. The underlying mechanism through which cyclic AMP exerts its effects appears to be maintenance of vascular homeostasis in the graft. A distinct adaptive mechanism triggered in the endothelium by hypoxia is expression of the cytokine interleukin-6 (IL-6) by a novel mechanism involving transcription driven by the nuclear factor IL-6 (NF-IL-6) DNA binding site in the promoter. IL-6 may exert protective effects on vascular function, thereby limiting vascular injury by a different mechanism than those recruited by elevated cAMP levels. These studies provide insights into tow independent mechanisms through which endothelium responds to oxygen deprivation, and suggest possible new approaches to attentuate vascular injury associated with ischemia.
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PMID:Hypoxia-induced modulation of endothelial cell properties: regulation of barrier function and expression of interleukin-6. 902 16

Tenidap is a structurally novel antirheumatic agent with anti-inflammatory and analgesic properties. Previous studies have shown that tenidap is able to inhibit the production and action of cytokines such as interleukin-1, interleukin-6 (IL-6) and tumour necrosis factor alpha. However, the mechanisms by which tenidap inhibits cytokine synthesis are not yet known. We investigated in the human astrocytoma cell line U373 whether tenidap inhibits IL-6 synthesis by inhibition of certain signal transduction processes leading to IL-6 synthesis. Cells were stimulated with different substances which have previously been shown to activate protein kinase A or C, reactive oxygen intermediates as well as transcription factors such as nuclear factor kappa B and AP-1 and which all result in IL-6 synthesis. Tenidap was a very potent inhibitor of IL-6 synthesis independent of the stimuli used, suggesting an inhibitory mechanism other than inhibition of a certain signal transduction pathway. Since IL-6 has been shown to be involved in the etiopathology of Alzheimer's disease and since the use of nonsteroidal anti-inflammatory drugs appears to be of therapeutical benefit, it is concluded that tenidap should be tested in clinical trials in order to determine whether it may be useful for the treatment of Alzheimer's disease.
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PMID:Potent inhibition of interleukin-6 expression in a human astrocytoma cell line by tenidap. 908 60


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