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)

Subclinical lymphocytic choriomeningitis virus infection primes mice expressing a V beta 8.1D beta 2J beta 2.3C beta 2 T cell receptor as a transgene for induction of fatal hematogenous shock after administration of a dose of staphylococcal enterotoxin B (SEB) that is tolerated by uninfected controls. The lethal effect is greatly diminished by prior depletion of the virus-primed CD4+ T cells. Evidence of transient tumor necrosis factor (TNF) secretion is detected in serum within 1 h of SEB administration, and massive amounts of interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) are present within 4-6 h. Mice are partly protected by treatment with dimeric soluble TNF receptor-Fc fusion protein or the nitric oxide synthase inhibitor, aminoguanidine, neither of which blocks SEB-induced IFN-gamma or IL-6 production. Administration of a monoclonal antibody to IFN-gamma concomitant with SEB effectively neutralizes this cytokine but has no effect on survival.
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PMID:Superantigen shock in mice with an inapparent viral infection. 796 12

Treatment of rats with bacterially derived lipopolysaccharide (LPS), a condition that mimics acute endotoxemia, results in a significant increase in the number of endothelial cells and macrophages in the liver. This is correlated with the release of proinflammatory and cytotoxic mediators that induce liver damage. In the present studies, we analyzed the effects of various inflammatory mediators released during the pathogenesis of hepatic injury on proliferation of liver nonparenchymal cells. To induce acute endotoxemia female Sprague-Dawley rats were injected intravenously with 5 mg/kg LPS. Endothelial cells and macrophages were isolated 48 h later by combined collagenase and pronase perfusion of the liver followed by centrifugal elutriation. Interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) had no effect on proliferation of either endothelial cells or macrophages. In contrast, whereas interleukin-1 beta (IL-1 beta) inhibited the proliferation of endothelial cells from untreated rats, this cytokine stimulated the growth of cells from endotoxemic rats. The colony-stimulating factors, granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF), also markedly enhanced the proliferation of endothelial cells, as well as macrophages from endotoxemic rats. Macrophages from endotoxemic rats were more sensitive to the colony-stimulating factors than cells from untreated rats. In contrast, the inflammatory mediators LPS and interferon-gamma (IFN-gamma) inhibited endothelial cell and macrophage growth, an effect that was partially blocked in endothelial cells by the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). This suggests that growth inhibition in these cells is mediated, in part, by nitric oxide. Interestingly, in both endothelial cells and macrophages from endotoxemic rats, GM-CSF, M-CSF, and IL-1 beta synergized with LPS and IFN-gamma to induce nitric oxide production. This was correlated with a further inhibition of proliferation that was partially reversed by L-NMMA in endothelial cells but not macrophages. Taken together these data demonstrate that endothelial cell and macrophage proliferation in the liver is controlled by a variety of mediators released during endotoxemia; however, the mechanisms regulating growth in the two cell types are distinct.
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PMID:Regulation of hepatic endothelial cell and macrophage proliferation and nitric oxide production by GM-CSF, M-CSF, and IL-1 beta following acute endotoxemia. 814 21

Tumor necrosis factor-alpha (TNF-alpha) is released in inflammatory lung conditions, raising airway nitric oxide (NO) concentrations through the cytokine-mediated induction of nitric oxide synthase (NOS). Cardiopulmonary bypass (CPB) creates an inflammatory state, characterized by the release of TNF-alpha, that may result in lung injury following CPB. This study measured plasma levels of TNF-alpha and interleukin-6 (IL-6) as well as airway NO concentrations during CPB, and the effect of methylprednisolone (MPSS) on the levels of these inflammatory products. Twenty adult males scheduled for coronary artery bypass grafting (CABG) were anesthetized and randomized to a group given MPSS at 1 gm intravenously 5 min before CPB (Group S) or a group not given MPSS (Group N). Plasma levels of TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA) and the airway NO concentration by chemiluminescence. TNF-alpha was significantly (p < 0.05) increased at 30 min after the termination of CPB, while IL-6 was significantly (p < 0.05) increased at 50 min into CPB and 30 min after the end of CPB in Group N as compared with controls in the same group and with Group S at the same time intervals. A group of 10 patients undergoing repair of infrarenal aortic aneurysms, which served as a control group for plasma levels of TNF-alpha, showed no significant changes in TNF-alpha concentrations at any time during aneurysm repair. Airway NO increased significantly (p < 0.01) in Group N as compared with Group S at 5, 20, 35, and 50 min of CPB.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucocorticoid reduction of bronchial epithelial inflammation during cardiopulmonary bypass. 852 Jul 38

The release of free radicals and pro-inflammatory cytokines such as nitric oxide (NO) and tumor necrosis factor alpha (TNF alpha) is commonly observed in adult respiratory distress syndrome (ARDS) following infection or exposure to microbial products. The aim of this study was to scrutinize the involvement of NO in ARDS in a mouse model determined by the sequential exposure to lipopolysaccharide (LPS) and formyl-norleucyl-phenylalanine (FNLP). Nitrite measurements in bronchoalveolar lavage fluids (BALF) and sera demonstrated that exposure to microbial products elicits large amounts of NO in LPS/FNLP-challenged mice. This release was significantly inhibited by infusion with the inducible NO synthase antagonist, aminoguanidine (AG). Our results show that LPS/FNLP exposure induces lung damage as demonstrated by protein and lactate dehydrogenase (LDH) increases in BALF. Liver damage was also detected in LPS/FNLP-challenged mice with increases in serum ornithine-carbamoyltransferase (OCT) levels. LPS/FNLP infusion led to elevated levels of the cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) in the sera. LPS/FNLP also led to neutrophil adhesion in the lung vasculature, as seen by increased levels of myeloperoxydase. Interestingly, inhibition of NO release in challenged mice led to an important increase in markers of tissue damage in the lungs and livers, but a decrease in neutrophil recruitment. Infusion of AG in LPS/FNLP-challenged mice led to a much increased level of sera TNF alpha. These data suggest that after exposure to microbial products, NO generated as a result of activation of the inducible NO synthase blocks the full expression of tissue damage in the lungs.
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PMID:The involvement of nitric oxide in a mouse model of adult respiratory distress syndrome. 854 74

The present study determined the plasma ACTH and corticosterone responses of the rat to acute local inflammation induced by the im injection of a small volume of turpentine. In response to tissue injury, ACTH and corticosterone concentrations rose rapidly, peaked at 1 h, and returned toward basal values by 3 h after turpentine injection. As acute inflammation developed, plasma interleukin-6 bioactivity increased significantly, and ACTH and corticosterone levels exhibited a secondary rise. These secondary responses were maximum 6-12 h after turpentine administration, persisted for 20-28 h, and were statistically significant regardless of the normal circadian variations in ACTH and corticosterone secretion. Injection of neutralizing anti-CRF antiserum 7 h after turpentine produced a complete reversal, whereas antiarginine vasopressin (anti-AVP) caused a partial (approximately 40%) inhibition, of inflammation-induced ACTH secretion. The cyclooxygenase inhibitor, ibuprofen (10 mg/kg, iv), like CRF antiserum, rapidly and completely reversed turpentine-induced ACTH secretion. In contrast, the nitric oxide synthase inhibitor, Nw-nitro-L-arginine methyl ester (30 mg/kg, iv), produced a significant enhancement of the ACTH response within 30 min of its injection. Measurement of plasma interleukin-6 bioactivity and fever showed that neither anti-CRF, anti-AVP, ibuprofen, nor Nw-nitro-L-arginine methyl ester acutely influenced the local inflammatory process itself, suggesting that these agents interacted directly with the hypothalamo-pituitary-adrenal axis. These data demonstrate that the ACTH response to local inflammation is mediated by synergistic actions of CRF and AVP, and that both stimulatory (PGs) and inhibitory (nitric oxide) intermediates regulate this response.
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PMID:Corticotropin-releasing factor, vasopressin, and prostaglandins mediate, and nitric oxide restrains, the hypothalamic-pituitary-adrenal response to acute local inflammation in the rat. 859 89

The effects of inflammatory cytokines (interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha) on energy metabolism were studied in primary cultured rat hepatocytes. Adenine nucleotide (ATP, ADP, and AMP) content, lactate production, the ketone body ratio (acetoacetate/beta-hydroxybutyrate) reflecting the liver mitochondrial redox state (NAD+/NADH), and nitric oxide formation were measured. Insulin increased ATP content in hepatocytes and had a maximal effect after 8-12 h of culture. Both interleukin-1beta and interleukin-6, but not tumor necrosis factor-alpha, significantly inhibited the ATP increase time- and dose-dependently. Interleukin-1beta and interleukin-6 also stimulated lactate production. During the same period, interleukin-1beta but not interleukin-6 decreased the ketone body ratio. Furthermore, interleukin-1beta markedly stimulated nitric oxide formation in hepatocytes, and this increase was blocked by NG-monomethyl-L-arginine (a nitric oxide synthase inhibitor) and by interleukin-1 receptor antagonist. NG-monomethyl-L-arginine reversed inhibition of the ATP increase, decrease in the ketone body ratio, and increase in lactate production, which were induced by interleukin-1beta. Interleukin-1 receptor antagonist completely abolished all of the effects induced by interleukin-1beta. These results demonstrated that interleukin-1beta and interleukin-6 affect the insulin-induced energy metabolism in rat hepatocytes by different mechanisms. Specifically, interleukin-1beta inhibits ATP synthesis by causing the mitochondrial dysfunction, a process which may be mediated by nitric oxide.
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PMID:Regulation of energy metabolism by interleukin-1beta, but not by interleukin-6, is mediated by nitric oxide in primary cultured rat hepatocytes. 860 98

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

beta-Amyloid protein (A beta) is the major component of the senile plaques in Alzheimer's disease (AD), and microglial cells have been shown to be closely associated with these plaques. However, the roles of A beta and microglial cells in pathogenesis of AD remain unclear. Incubation of rat microglial cells with A beta(1-40) caused a significant increase in nitrite, a stable metabolite of nitric oxide (NO), in culture media, while there was no detectable increase in nitrite in astrocyte-rich glial cells or cortical neurons after incubation with A beta(1-40). Nitrite production by microglial cells was also induced by A beta(1-42), but not A beta(25-35). An inhibitor of NO synthase, NG-monomethyl-L-arginine (NMMA), as well as dexamethasone and actinomycin D, dose-dependently inhibited this nitrite production. Among the various cytokines investigated such as interleukin-1, interleukin-6, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma), only IFN-gamma markedly enhanced A beta-dependent nitrite production. Cultured cortical neurons were injured by microglial cells stimulated with A beta in a dose-dependent manner in the presence of IFN-gamma. Neurotoxicity caused by the A beta plus IFN-gamma-stimulated microglial cells was significantly attenuated by NMMA. Thus, although further investigations into the effect of A beta on human microglial cells are needed, it is likely that A beta-induced NO production by microglial cells is one mechanism of the neuronal death in AD.
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PMID:beta-Amyloid protein-dependent nitric oxide production from microglial cells and neurotoxicity. 878 1

Activated macrophages have been shown to exert cytostatic and cytotoxic effects toward tumor cells via nitric oxide (NO) release. In the CNS, microglial cells are considered to be the main resident population of immune effector cells. In this study, cytotoxic activity of N11, an immortalized murine microglial cell line, toward rat progressive DHD/PROb and regressive DHD/REGb colon carcinoma cells was examined in parallel with NO production. Cytotoxicity was evaluated using a novel method, the gamma-glutamyl transpeptidase (gamma-GTP) assay, based on the fact that DHD tumor cells expressed high levels of gamma-GTP activity, while no gamma-GTP activity was found in cells of the monocyte/macrophage lineage. Results showed that activation of N11 cells by interferon-gamma plus either lipopolysaccharide or tumor necrosis factor-alpha induced high amounts of NO release and cytotoxic effects toward DHD/PROb as well as DHD/REGb cells. NO release by activated N11 cells was augmented by addition of tumor cell-conditioned medium. Both NO release by N11 cells and cytotoxicity were blocked by addition of N(G)-monomethyl-L-arginine (L-NMA), an inhibitor of NO synthase, suggesting that cytotoxicity was mediated by N11-derived NO. However, in the presence of L-NMA an increased production of interleukin-6 was also observed. In conclusion, in opposition to information obtained with brain-derived endothelial cells, brain-derived microglial cells did not differentiate between progressive and regressive clones of colon carcinoma cells. Our results point to a specific role for both endothelial and microglial cell types in the context of brain metastasis. Microglial cells can be cytotoxic for tumor cells, and this cytotoxicity is mediated by NO.
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PMID:Microglial cells induce cytotoxic effects toward colon carcinoma cells: measurement of tumor cytotoxicity with a gamma-glutamyl transpeptidase assay. 900 56

Pro-inflammatory cytokines, such as tumour necrosis factor (TNF) and free radicals, such as nitric oxide (NO), are mediators of endotoxaemia. Catecholamines are in clinical use to treat the haemodynamic consequences of severe septic shock. Beta-adrenergic agonists exert many of their effects by elevation of intracellular cyclic AMP (cAMP) concentration. Cyclic AMP can modulate endotoxin-induced cytokine and NO production. Here we investigate the effect of isoproterenol pretreatment on the cytokine and NO production induced by bacterial lipopolysaccharide (LPS, 4-10 mg/kg). Pretreatment with isoproterenol (10 mg/kg) blunted the LPS-induced TNF response, increased the LPS-induced formation of interleukin-10 and interleukin-6 and reduced the LPS-induced production of NO in conscious mice. In anaesthetized rats, pretreatment with isoproterenol prevented the LPS-induced suppression of vascular contractility to norepinephrine in the thoracic aorta ex vivo. The hyporeactivity is due to expression of the inducible isoform of NO synthase (iNOS) and was restored by in vitro administration of NG-methyl-L-arginine (L-NMA), an inhibitor of NO synthase. However, L-NMA did not alter vascular contractility in control vessels or in rings taken from the LPS-treated rats pretreated with isoproterenol. Our findings suggest that, in addition to its haemodynamic actions, isoproterenol may also exert beneficial effects by modulating the endotoxin-induced inflammatory response.
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PMID:Isoproterenol regulates tumour necrosis factor, interleukin-10, interleukin-6 and nitric oxide production and protects against the development of vascular hyporeactivity in endotoxaemia. 903 18


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