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)

There is increasing experimental and clinical evidence that a number of cytokines play a major role in the response to injury and infection and in the development of organ damage in critically ill patients. Tumour necrosis factor (TNF) is now proposed to be a key mediator of organ injury during sepsis. It is elevated early in the course of septic shock and high levels correlate with unfavourable outcome. In animals it can produce the effects of endotoxin. The prophylactic administration of anti-TNF antisera protects mice and rabbits from lethal effects of lipopolysaccharide. Interleukin-1 (IL-1) is an endogenous pyrogen which induces leukocytosis and muscle catabolism. It causes hypotension and tachycardia by reducing smooth muscle contractility. IL-1 receptor blockers have been shown to diminish mortality in experimental endotoxic shock. Interleukin-6 (IL-6) is a pyrogen and lymphocyte activator. It is the major stimulus to acute phase protein production by the liver. A recently described neutrophil-activating peptide (Interleukin-8; IL-8) may be involved in the pathogenesis of ARDS. High blood levels of IL-8 have been found in patients with septic shock. Platelet-derived growth factor (PDGF) has been shown to stimulate TNF production, leukocyte chemotaxis and pulmonary vasoconstriction in response to endotoxin. Other cytokines and growth factors have not yet been studied in critical illness. The cytokine network can be either protective or damaging. Its activation during critical illness triggers complex and still poorly understood interactions. A better comprehension of its role in protection from infection and in the pathogenesis of multiple organ failure may allow therapeutic manipulations aimed at minimising adverse effects while retaining immunological protection.
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PMID:The cytokine network in the critically ill. 152 67

Recent studies in alcoholic hepatitis have proposed a role for the cytokine tumour necrosis factor-alpha (TNF-alpha) a mediator of endotoxic shock in sepsis. In this study plasma levels of the closely related cytokine interleukin-6 (IL-6) were assayed in 96 samples from 58 patients with severe alcoholic hepatitis, and 69 patients in control groups (21 normal, 10 alcoholic without liver disease, 10 inactive alcoholic cirrhosis, 18 chronic liver disease, 10 chronic renal failure). Plasma IL-6 levels were markedly elevated in patients with alcoholic hepatitis when compared with all control groups (P less than 0.001). IL-6 levels were higher in patients who died (P = 0.04) and correlated with the features of severe disease including: increased grade of encephalopathy, increased neutrophil count, increased prothrombin ratio, hypotension, increased serum creatinine and increased serum bilirubin. Surprisingly, no correlation was found between levels of plasma IL-6 and plasma TNF-alpha or endotoxin, or the presence of infection; an inverse correlation was found between plasma IL-6 and serum globulins. These findings provide further evidence that the IL-6/TNF cytokine system is activated in severe alcoholic hepatitis and may mediate hepatic or extra-hepatic tissue damage.
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PMID:Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis. 204 24

Cytokines have significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In the present study, we examined both the early and delayed effects of interleukin-6 (IL-6) on cultured chick embryo ventricular myocytes. Exposure of these cells to human recombinant IL-6 significantly decreased peak systolic [Ca2+]i (71.0 +/- 0.6% of the control value) and the amplitude of cell contraction (66.0 +/- 7.4% of the control value) within a few minutes. Pretreatment with NG-monomethyl-L-arginine (L-NMMA) or methylene blue completely inhibited the IL-6-induced early changes. Subsequent addition of L-arginine reversed the effects of L-NMMA. The levels of cGMP were significantly increased after 30 minutes of exposure to IL-6 (134.4 +/- 9.1% of the control value). Pretreatment with L-NMMA or EGTA significantly inhibited the IL-6-induced early elevation of cGMP. These results suggest that IL-6 acutely decreases intracellular Ca2+ transients and depresses cell contraction by nitric oxide (NO)-cGMP-mediated pathway. Therefore, IL-6 may enhance the Ca(2+)-dependent constitutive NO synthase activity in cardiac myocytes. On the other hand, 24-hour exposure to IL-6 also increased the levels of cGMP (159.0 +/- 22.8% of the control value) regardless of pretreatment with EGTA. These delayed increases in cGMP were also shown to be coupled with decreases in intracellular Ca2+ transients and the amplitude of cell contraction. Thus, IL-6 may induce Ca(2+)-independent NO synthase in cardiac myocytes. Together with the previous reports that have suggested the possible roles of IL-6 in myocardial stunning or endotoxic shock, this negative inotropic effect of IL-6 may contribute to these clinical settings.
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PMID:Nitric oxide-mediated effects of interleukin-6 on [Ca2+]i and cell contraction in cultured chick ventricular myocytes. 751 62

Vascular endothelial cell (EC) injury by lipopolysaccharides (LPS) plays a major role in the pathogenesis of gram-negative bacterial sepsis and endotoxic shock. The studies described here were performed to define further the molecular mechanisms involved in the EC responses to LPS. We showed that serum was required for LPS-mediated cytotoxicity for bovine brain microvessel, pulmonary, and aortic ECs and that anti-human CD14 antibodies completely blocked LPS-mediated cytotoxicity for ECs in the presence of human serum. The addition of a recombinant soluble form of human CD14 to serum-free medium restored the LPS-mediated cytotoxicity, whereas the addition of LPS binding protein (LBP), a serum protein that potentiates LPS-induced responses to monocytes, had no effect. A similar dependency on serum or recombinant soluble CD14 (under serum-free conditions) was observed for LPS-induced secretion of interleukin-6 by human umbilical vein ECs. These findings indicate that soluble CD14 is required for LPS-mediated EC responses independently of LPB, suggesting that serum soluble CD14 represents a naturally occurring agonist for EC responses to LPS.
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PMID:Endotoxin-mediated endothelial cell injury and activation: role of soluble CD14. 768 81

Bactericidal/permeability-increasing protein (BPI), a human neutrophil granule protein, has been shown to bind lipopolysaccharide (LPS) and neutralize LPS-mediated cytokine production in adherent monocytes and the whole-blood system. In this study we investigated the ability of recombinant human BPI (rBPI) to inhibit LPS-induced vascular endothelial cell (EC) injury and activation. rBPI inhibited significantly both rough and smooth LPS-mediated injury for cultured bovine brain microvessel ECs, as measured by lactic dehydrogenase release, and blocked the LPS-induced interleukin-6 (IL-6) release from human umbilical vein ECs in a dose-dependent manner. BPI was able to inhibit LPS-mediated EC injury or activation whether it was added before or at the same time with LPS, but delaying the time of addition of rBPI resulted only in a partial inhibition. BPI also inhibited LPS-induced tumor necrosis factor alpha, IL-1 beta, and IL-6 release from human whole blood. This inhibition of tumor necrosis factor alpha, IL-1 beta, and IL-6 release from whole blood was maximal when BPI was premixed with LPS before addition to blood and was partial when BPI was added simultaneously with LPS, but no inhibition was observed when the addition of rBPI was delayed for 5 min. These findings suggest that rBPI is a potent inhibitor of LPS-mediated responses in ECs and whole blood and underscore the potential use of BPI in treatment or prevention of endotoxic shock. In contrast, the anti-lipid A monoclonal antibodies HA-1A and E5 were ineffective in inhibiting LPS-mediated EC injury and activation as well as LPS-induced cytokine release in whole blood.
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PMID:Bactericidal/permeability-increasing protein protects vascular endothelial cells from lipopolysaccharide-induced activation and injury. 806 10

Rat neonatal mortality to endotoxin and age-related changes in adherent splenic cell mediator production in vitro were investigated. Neonatal rat pups, 24, 48, 96, and 216 h old or maternal adult rats were administered doses of Salmonella enteritidis endotoxin, (.024 mg to 7.5 mg/kg) and survival was monitored for 72 h. Mortality demonstrated high sensitivity (p < .05) of neonates to endotoxin (particularly 24 h old neonates). Endotoxin administration .6 mg/kg intracardiac) produced a 100% lethality in 24 h neonates (p < .05) versus 23% or less lethality in the 48 to 216 h old age group. Endotoxin administration (.4 mg/kg subcutaneous) also produced 100% lethality in 24 h old neonates compared with reduced mortality versus older age groups. Endotoxin in vitro stimulated (p < .05) adherent splenic cell thromboxane (TX)B2, interleukin-6, and nitrite production in most groups. Splenic cell nitrite production was higher (p > .05) in the 24 h old neonates, but lower in 48 h and 96 h old groups compared with maternal adults. Splenic cell TXB2 production was higher (p < .05) in the 24 h and 216 h old neonates relative to maternal adults. In conclusion, 24 h old rat pups are more susceptible to endotoxic shock than older age groups and adults, and exhibit altered production of the cellular mediators nitric oxide and TXB2.
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PMID:Age-related mortality and adherent splenic cell mediator production to endotoxin in the rat. 860 3

The immunomodulating capacity of the methylxanthine A802715 (5-hydroxy-5-methyl)hexyl-3-methyl-7-propylxanthin) was investigated in various murine models of endotoxemia and compared with that of the chemically related reference compound pentoxifylline. At a dose of 180 mg/kg both compounds protected mice against a lethal shock dose of lipopolysaccharide (LPS) (5 mg/kg) in nonsensitized mice and against LPS (5 micrograms/kg)-initiated liver failure in D-galactosamine (700 mg/kg)-sensitized animals. The methylxanthines attenuated systemic release of endogenous tumor necrosis factor (TNF) and interferon-gamma during endotoxic shock, and potently up-regulated early production of circulating interleukin-10 and interleukin-6. Treatment of mice with A802715 alone induced levels of circulating soluble TNF receptors (sTNF-R p55 and p75) 3- to 4-fold higher than those of controls. This increase was additive to the one elicited by LPS. Moreover, pentoxifylline and A802715 prevented liver injury due to intravenous injection of recombinant TNF in D-galactosamine-sensitized mice. In primary cultures of murine hepatocytes, A802715 (500 microM) as well as other cAMP-raising compounds conferred protection from TNF cytotoxicity. We concluded that, in addition to a direct target cell protection via an increase in intracellular cAMP, methylxanthines prevented the systemic toxicity of LPS in mice by a further principle, i.e., by a shift of the humoral response to LPS in favor of an enhanced release of immunosuppressive cytokines.
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PMID:Enhanced release of interleukin-10 and soluble tumor necrosis factor receptors as novel principles of methylxanthine action in murine models of endotoxic shock. 876 78

Interleukin-1 (IL-1) and ibuprofen modulate the host response in different models after endotoxic challenge. A comparative study was made between the two drugs, as they were jointly administered, to explore a potentiation of their therapeutic effects. Endotoxic challenge was provoked in CBA/H mice with lipopolysaccharide (LPS) from Escherichia coli (125 mg/kg), with administration of recombinant murine IL-1 beta (80 ng/mouse) 24 hr pre-LPS. Two doses of ibuprofen (1 mg/kg) were administered 1 hr before and 30 min after the septic challenge. Serum levels of IL-1 alpha, tumor necrosis factor-alpha (TNF alpha), and interleukin-6 (IL-6) were determined 1,2, and 4 hr, post-LPS, and prostaglandin E2 (PGE2) urine levels 4,8, and 12 hr post-LPS, and a comparative mortality study was performed. IL-1 beta treatment provoked a reduction of IL-1 alpha, TNF alpha, and IL-6 without affecting PGE2, while ibuprofen provoked a later increase of IL-1 alpha, TNF alpha, and IL-6, with a decrease of PGE2. Both drugs caused a notable enhancement of survival, with no difference between them, but their combined administration caused no improvement. We conclude that both drugs exert a similar therapeutic effect in endotoxic shock by different mechanisms.
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PMID:Differential effects of IL-1 beta and ibuprofen after endotoxic challenge in mice. 907 68

Tissue factor pathway inhibitor (TFPI) is a Kunitz-type plasma protease inhibitor that inhibits factor Xa and the factor VIIa/tissue factor catalytic complex. It plays an important role in feedback inhibition of the coagulation cascade (Broze, Annu Rev Med 46:103, 1995). TFPI has also been used successfully to prevent lethality and attenuate coagulopathic responses in a baboon model of septic shock (Creasey et al, J Clin Invest 91:2850, 1993; and Carr et al, Circ Shock 44:126, 1995). However, the mechanism of reduced mortality in these animals could not be explained merely by the anticoagulant effect of TFPI, because TFPI-treated animals also had a significantly depressed interleukin-6 response. Moreover, inhibition of coagulopathic responses by other anticoagulants has failed to block the organ damage or lethal effect of endotoxic shock (Coalson et al, Circ Shock 5:423, 1978; Warr et al, Blood 75:1481, 1990; and Taylor et al, Blood 78:364, 1991). We show here that recombinant TFPI can bind to endotoxin in vitro. This binding prevents interaction of endotoxin with both lipopolysaccharide binding protein and CD14, thereby blocking cellular responses.
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PMID:Tissue factor pathway inhibitor blocks cellular effects of endotoxin by binding to endotoxin and interfering with transfer to CD14. 919 48

Interfering with the endotoxin-mediated cytokine cascade is thought to be a promising approach to prevent septic complications in gram-negative infections. The synthetic lipid A analog SDZ MRL 953 has been shown to be protective against endotoxic shock and bacterial infection in preclinical in vivo models. As part of a trial of unspecific immunostimulation in cancer patients, we conducted a double-blind, randomized, vehicle-controlled phase I trial of SDZ MRL 953 to investigate, first, its biologic effects and safety of administration in humans and, second, its influence on reactions to a subsequent challenge of endotoxin (Salmonella abortus equi). Twenty patients were treated intravenously with escalating doses of SDZ MRL 953 or vehicle control, followed by an intravenous application of endotoxin (2 ng/kg of body weight [BW]). Administration of SDZ MRL 953 was safe and well-tolerated. SDZ MRL 953 itself increased granulocyte counts and serum levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but not of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8. Compared with vehicle control, pretreatment with SDZ MRL 953 markedly reduced the release of TNF-alpha, IL-1beta, IL-8, IL-6, and G-CSF, but augmented the increase in granulocyte counts to endotoxin. Induction of tolerance to the endotoxin-mediated cascade of proinflammatory cytokines by pretreatment with SDZ MRL 953 in patients at risk may help to prevent complications of gram-negative sepsis.
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PMID:Downregulation of the proinflammatory cytokine response to endotoxin by pretreatment with the nontoxic lipid A analog SDZ MRL 953 in cancer patients. 926 88


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