Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of PTH-induced bone loss is uncertain. Experimental evidence suggests that PTH induces the production by osteoblasts of the bone-resorbing cytokine, interleukin-6. We measured the circulating levels of interleukin-6, tumor necrosis factor-alpha, and interleukin-1 beta and examined their relationship to biochemical markers of bone turnover in 38 patients with primary hyperparathyroidism (7 of whom also were studied after successful parathyroid adenomectomy), 6 patients with hypoparathyroidism, and 12 subjects with normal parathyroid function. The patients with untreated primary hyperparathyroidism had mean serum levels of interleukin-6 that were 16-fold higher than control values (mean +/- SEM; primary hyperparathyroidism 18.6 +/- 2.1 pg/mL, controls 1.1 +/- 0.1; P < 0.001). Circulating levels of interleukin-6 soluble receptor (primary hyperparathyroidism 41.7 +/- 1.2 ng/ mL, controls 25.1 +/- 1.0; P < 0.001), and tumor necrosis factor-alpha (primary hyperparathyroidism 11.6 +/- 0.8 pg/mL, controls 2.5 +/- 0.2; P < 0.001) were also elevated. After successful parathyroid adenomectomy, levels of each of these cytokines fell into the normal range. The mean levels of interleukin-6, its soluble receptor, and tumor necrosis factor-alpha in the subjects with hypoparathyroidism were lower than control values (P < 0.001 for each variable). There was no difference between subjects with primary hyperparathyroidism and controls in the circulating level of interleukin-1 beta. In the subjects with untreated primary hyperparathyroidism, serum levels of interleukin-6 correlated strongly with those of intact PTH (r = 0.47, P = 0.003) and biochemical markers of bone resorption: serum deoxypyridinoline (r = 0.93, P < 0.001), serum type I collagen carboxyterminal telopeptide (r = 0.87, P < 0.001), urinary pyridinoline (r = 0.81, P < 0.001), and urinary deoxypyridinoline (r = 0.63, P = 0.005). Levels of tumor necrosis factor-alpha correlated less strongly with the same variables: PTH (r = 0.41, P = 0.01), serum deoxypyridinoline (r = 0.48, P = 0.002), serum type I collagen carboxyterminal telopeptide (r = 0.46, P = 0.004), urinary pyridinoline (r = 0.61, P = 0.008), and urinary deoxypyridinoline (r = 0.61, P = 0.007). Levels of interleukin-6 also correlated with those of tumor necrosis factor-alpha (r = 0.44, P = 0.005). Multiple regression analysis indicated that interleukin-6, but not tumor necrosis factor-alpha, was independently predictive of bone resorption. We conclude that serum levels of interleukin-6 and tumor necrosis factor-alpha are increased in patients with primary hyperparathyroidism and are normalized by successful surgical treatment. The finding that these cytokines correlate with biochemical markers of bone resorption suggests that they play a role in the pathogenesis of bone loss in primary hyperparathyroidism.
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PMID:Circulating levels of interleukin-6 and tumor necrosis factor-alpha are elevated in primary hyperparathyroidism and correlate with markers of bone resorption--a clinical research center study. 885 82

During adult cardiac surgery the plasma pro-inflammatory cytokine response is balanced by a phased anti-inflammatory cytokine response. Whether a similar balanced plasma pro- and anti-inflammatory cytokine response occurred in paediatric cardiac surgery was investigated. Changes in intra-pulmonary cytokine balance by measuring bronchoalveolar lavage (BAL) cytokine content were also estimated. Plasma and BAL samples were obtained from 10 children (aged 15 months to 10 years) 10 min after induction of anaesthesia (sample 0), 5 min after the onset of cardiopulmonary bypass (CPB) (sample 1), 10 min after release of the aortic cross clamp (sample 2), and 2 and 24 h after the end of CPB (samples 3 and 4). BAL and plasma was assayed for interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), IL-8, IL-10, interleukin 1 receptor antagonist (IL-1ra) and the TNF soluble receptors (TNFsrs). There was a phased plasma anti-inflammatory response commencing with IL-10 (sample 2), and followed by significant increases in IL-1ra (samples 3, 4 and 5) and TNF soluble receptors (sample 5). Plasma TNF-alpha and IL-1 beta concentrations were not significantly elevated from baseline. Mean baseline plasma IL-8 was 30 (SEM 9) pg/ml. This was significantly elevated at sample 4 (112 (SEM 68) pg/ml). In BAL, only IL-8 and IL-10 were significantly elevated after CPB as compared with baseline. During paediatric cardiac surgery there is a significant increase in plasma and BAL IL-8. This is balanced within the plasma by a phased anti-inflammatory cytokine response, and within the lung by IL-10.
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PMID:The balance of pro and anti-inflammatory cytokines in plasma and bronchoalveolar lavage (BAL) at paediatric cardiac surgery. 893 84

IFN-gamma is a potent pro-inflammatory cytokine involved in the immunologic rejection of transplanted organs. Having previously demonstrated differential suppressive effects of methylprednisolone (MP), prednisolone (P) and cyclosporine (CsA) on dialysis patients' lymphocyte proliferative responses to phytohaemagglutinin (PHA), we studied the effects of these drugs on dialysis patients' lymphocyte IFN-gamma production during mitogenic and allogeneic (MLR) stimulation. The mean +/- SEM 50% inhibitory concentration (ng/ml) on cell proliferation was significantly lower for MP than P in PHA-stimulated haemodialysis (HD) patients' (35 +/- 7 vs 152 +/- 25, P < 0.001) and peritoneal dialysis (PD) patients' (35 +/- 11 vs 134 +/- 33, P = 0.001) cultures and in HD patients' MLR cultures (15 +/- 3 vs 48 +/- 9, P < 0.001). The mean +/- SEM fractional responses (PHA or MLR + drug/PHA or MLR) in culture supernatant IFN-gamma concentrations were significantly lower with 10(-7) M concentrations of MP than P in HD (0.19 +/- 0.05 vs 0.31 +/- 0.06, P = 0.01) and PD (0.30 +/- 0.11 vs 0.46 +/- 0.11, P < 0.05) PHA cultures and in HD MLR cultures (0.15 +/- 0.04 vs 0.28 +/- 0.07, P = 0.01). CsA (400 ng/ml) alone not only caused less than 50% inhibition of IFN-gamma production in 15/27 HD PHA, 6/14 PD PHA and 4/13 HD MLR cultures, but actually stimulated it in 9 HD and 5 PD PHA cultures. The results suggest that: (1) MP has greater immunosuppressive potential than P for renal transplant recipients; (2) the stimulation of IFN-gamma by CsA in some patients could be harmful in patients with initial allograft dysfunction; and (3) pre-transplant in-vitro assessment of recipients' PBMC responsiveness to glucocorticoids and CsA may help individualize the post-transplant immunosuppressive regimen.
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PMID:Differential suppression of dialysis patients' lymphocyte IFN-gamma production by glucocorticoids and cyclosporine. 898 Aug 83

While the regulation of nitric oxide (NO) by inflammatory cytokines or lipopolysaccharide (LPS) has received considerable attention, NO modulation of cytokine expression has yet to be fully explored. The NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), inhibited interleukin (IL)-8 and IL-6 production in LPS-stimulated human whole blood in a dose-dependent manner. In the presence of 1 microgram/mL LPS, L-NAME blocked IL-8 release (72 +/- 4% inhibition at 20 mM (mean +/- SEM, p < .05)) 24 h post-LPS without affecting cellular viability. IL-6 production was significantly inhibited only with the highest dose of L-NAME used. L-NAME inhibition of IL-8 production was also observed at the mRNA level. Conversely, direct exposure of whole blood to NO with the spontaneous NO liberator DETA NONOate caused a dose-dependent stimulation of IL-8, but had no effect on IL-6 release. IL-8 concentrations rose from 8.3 +/- 1.9 ng/mL at 24 h to 31.7 +/- 7.6 ng/mL at 72 h with a single stimulation of 10 mM DETA NONOate. The hydroxyl radical scavenger dimethyl sulfoxide (DMSO) prevented the DETA NONOate induction of IL-8, suggesting the participation of the hydroxyl radical in the NO-induced IL-8 production. These results provide important evidence substantiating a role for NO as a regulator of cytokine expression.
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PMID:Nitric oxide regulation of interleukin-8 gene expression. 898 33

Although elevated concentrations of a few cytokines have been shown to be present in the bronchoalveolar lavage (BAL) fluid (BALF) of patients with the acute (adult) respiratory distress syndrome (ARDS), the pathogenesis of ARDS is largely unknown. Leukaemia inhibitory factor (LIF), a growth factor recently recognised as a polyfunctional cytokine integrated in cytokine networks was measured in unconcentrated BALF of patients from different patient groups. LIF was measured in BALF by means of a specific and sensitive ELISA (detection limit 10 pg/ml) in BALF (lavage of 3 x 50 ml in the right middle lobe). LIF was not detected in the BALF of 13 healthy control patients and in only one (34 pg/ml) out of 25 patients at risk for ARDS (after cardiopulmonary bypass surgery) who underwent BAL 4 h after the end of the extracorporeal circulation. High and detectable levels were found in the unconcentrated BALF of 10 out of 12 patients with full-blown ARDS (212 +/- 116, mean +/- SEM, range 10-985 pg/ml). There was a good correlation between the level of LIF in the BALF and a number of markers of inflammation such as neutrophils/ml, albumin and protein levels. The biological role of LIF in these BALFs is not readily explained by its currently known actions and it is unknown whether LIF contributes to or is a response to local tissue damage. Our results indicate that this cytokine is part of the inflammatory cytokine cascade in ARDS.
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PMID:High levels of leukaemia inhibitory factor in ARDS. 904 84

The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale < or = 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even-numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin-1 beta, interleukin-6 (IL-6), tumor necrosis factor alpha, alpha 1-acid-glycoprotein, C-reactive protein, and albumin. Time-invariant and time-variant Michaelis-Menten models were fit to the phenytoin concentration-time data. Protein intake was closely monitored. The mean (+/- SEM) unbound fraction of phenytoin increased from 0.17 +/- 0.02 on day 1 to 0.24 +/- 0.04 on day 10 (P < 0.05). The time-variant model was superior in describing the concentration-time data of unbound phenytoin in eight of nine patients. Mean (+/- SEM) pharmacokinetic parameter estimates for unbound phenytoin were: Vmax delta = 605 +/- 92 mg/day, VmaxB = 149 +/- 26.3 mg/day, K(ind) = 0.013 +/- 0.004 hr-1. Interleukin-6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin-6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin-6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.
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PMID:Effect of acute phase response on phenytoin metabolism in neurotrauma patients. 905 39

With its antiinflammatory properties, interleukin (IL)-10 may play an important role in limiting complications associated with cardiopulmonary bypass (CPB). We previously demonstrated that pretreatment with steroids can significantly increase IL-10 production during CPB, but neither the heart nor the lung was found to be its main source. To define whether the liver is the source of IL-10, hepatic venous cannulation was performed in 12 patients undergoing CPB. Each patient received 30 mg/kg of methylprednisolone before operation. Plasma levels of IL-10 were simultaneously measured in peripheral arterial blood and hepatic venous blood before heparin administration, before aortic cross-clamping, and 5, 30, 60, 90, and 120 minutes after aortic declamping. The duration of CPB and aortic cross-clamping was 113 +/- 7 minutes and 75 +/- 6 minutes (mean +/- SEM), respectively. IL-10 levels 30 minutes after declamping were significantly higher in hepatic venous blood than in arterial blood (1187 +/- 573 pg/ml vs 911 +/- 405 pg/ml, p < 0.01 by Wilcoxon's signed-rank test). To determine whether steroids can also induce the release of another antiinflammatory cytokine, IL-4, plasma IL-4 levels were measured simultaneously. IL-4 was detected in the arterial blood of only 4 of the 12 patients, transiently after aortic declamping. IL-4 was not detected in hepatic venous blood. In conclusion, the liver is a major source of IL-10 during CPB. However, steroid-treated patients do not show an increase in IL-4, and the liver is not the source of IL-4 during and after CPB.
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PMID:Hepatic release of interleukin-10 during cardiopulmonary bypass in steroid-pretreated patients. 906 Aug 3

To identify the immunologic mechanisms that influence susceptibility to GN, we compared the severity of accelerated anti-glomerular basement membrane (GBM) nephritis between Lewis (LEW) and Brown Norway (BN) rats and analyzed differences in their immune responses to the nephritogenic immunoglobulin. Lewis (LEW) rats preimmunized with sheep IgG developed proliferative GN with marked proteinuria [peak protein excretion (mean +/- SEM) = 85.3 +/- 15.3 mg/24 hr; normal = 6.4 +/- 0.8 mg/24 hr] after receiving a subnephritogenic dose of sheep anti-rat GBM antiserum. Identically treated Brown Norway (BN) rats, on the other hand, had minimal renal pathology and minimal proteinuria (peak protein excretion = 22.6 +/- 3.1 mg/24 hr; normal = 13.0 +/- 0.6 mg/24 hr). Serum titers of rat anti-sheep IgG isotypes and intraglomerular binding of sheep IgG, rat IgG, and rat complement (C3) were comparable in both strains. In contrast, only LEW rats developed a strong cellular immune response to sheep IgG represented by intrarenal T lymphocyte (OX19+) and monocyte (ED1+) accumulation [LEW vs. BN (mean +/- SEM): OX19+ = 0.60 +/- 0.10 vs. 0.14 +/- 0.01 cells/glomerulus, control = 0.02 +/- 0.01; ED1+ = 4.0 +/- 0.4 vs. 1.0 +/- 0.2 cells/glom., control = 0.8 +/- 0.3] and a significant cutaneous delayed-type hypersensitivity (DTH) reaction [LEW versus BN (mean +/- SEM): delta ear thickness = 0.22 +/- 0.02 vs. 0.05 +/- 0.03 mm; control = 0.04 +/- 0.02 mm]. Upon rechallenge with sheep IgG in vitro, LEW splenocytes expressed a T helper 1 (Th1) cytokine pattern (IFN gamma and IL-2 mRNA, but little IL-4 mRNA) which is associated with delayed-type hypersensitivity reactions. BN splenocytes, on the other hand, expressed IL-4 in addition to IL-2 and IFN gamma mRNA that is consistent with an undifferentiated (Th0) cytokine profile. These studies suggest that humoral immunity to heterologous immunoglobulin planted in the kidney is not sufficient for full expression of accelerated anti-GBM nephritis, and that additional cellular immune mechanisms are required. We conclude that susceptibility to accelerated anti-GBM nephritis is strongly influenced by the host's propensity to mount a Th1-type response and DTH reaction to the disease-inciting immunoglobulin.
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PMID:Immunologic determinants of susceptibility to experimental glomerulonephritis: role of cellular immunity. 906 95

Daily systemic administration of hematopoietic growth factors can be associated with dose-limiting systemic side effects. To overcome this, we have investigated hematopoietic cytokine gene transfer to the marrow cavity of dogs by direct intramarrow injection of adenoviral vectors. In marrow culture, replication-deficient (E1-deleted) adenoviral vectors were able to transduce marrow stromal cells, demonstrating 30-fold greater expression than from other marrow cell types. High-level (ng/ml) cytokine production from transduced stromal cells persisted for 14 days in culture. Because adenovectors could efficiently transduce marrow stromal cells in culture, we investigated if stromal cells could also be transduced in vivo following direct intramarrow vector injection. Adenovectors with genes for interleukin 6 (IL-6) and Lac Z (beta-galactosidase) were injected directly into the marrow cavity of dogs resulting in protein expression localized to within the treated marrow. To evaluate this approach further in dogs, we constructed a vector expressing biologically active canine granulocyte-macrophage colony stimulating factor (GM-CSF). 293 cells infected with ADGM-CSF demonstrated prevalent GM-CSF mRNA by Northern blot and 135 +/- 30 ng/ml of protein as measured by enzyme-linked immunosorbent assay (ELISA). In vitro bioactivity of protein expressed was confirmed by canine GM colony-forming assay (CFU-GM). In vivo high-level protein production was noted in supernatants of marrow aspirates 72 hr following direct intramarrow administration of ADGM-CSF (baseline mean +/- SEM, 27 +/- 22 ng/ml, 72-hr sample 921 +/- 461 ng/ml). A localized myeloid expansion of marrow and significant peripheral leukocytosis (neutrophilia) were noted in all ADGM-CSF-treated dogs. Peripheral blood changes lasted for up to 3 weeks in dogs following single intramarrow injection. Thus, adenoviral cytokine expression from the marrow of a single large bone (ilium) led to compartmentalized expression of growth factor and an increase of hematopoiesis sufficient to cause peripheral blood changes in a large animal model.
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PMID:Intramarrow cytokine gene transfer by adenoviral vectors in dogs. 909 6

MS is a T-cell-mediated demyelinating disease of the CNS, in which the cytokine network may be deranged, leading to an altered immunoregulation. Tumor necrosis factor alpha (TNF-alpha) is a cytokine with several effects on the neuroimmune system. There are specific TNF-alpha receptors on human lymphocytes and other cell types, even in the CNS. We assayed TNF-alpha binding on peripheral blood T cells from MS patients compared with healthy subjects. T cells from MS patients have significantly more TNF-alpha receptors than those from control subjects (Bmax, 955 +/- 31 versus 126 +/- 3 [mean +/- SEM] receptors per cell). Such TNF-alpha binding sites are of the same type in patients and healthy subjects (Kd, 68.7 +/- 4.8 versus 70.2 +/- 4.1 [mean +/- SEM]pM). We discuss these results in terms of MS immunopathogenesis, because activated T cells have increased amounts of TNF-alpha receptors.
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PMID:T-cell tumor necrosis factor-alpha receptor binding in patients with multiple sclerosis. 910 63


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