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)

The cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are increased in the circulation of patients with chronic heart failure. However, their correlation with left ventricular dysfunction has not yet been thoroughly evaluated, and their interrelation with other neurohumoral systems, such as the adrenergic system and endothelin, is unclear. Therefore TNF-alpha, its soluble receptor II, IL-6, big endothelin, and noradrenaline levels were simultaneously measured in venous blood from 65 patients with heart failure in New York Heart Association (NYHA) class II to IV during therapy with digitalis, furosemide, and enalapril. TNF-alpha plasma levels were 3.2+/-0.2 SEM pg/ml in 38 patients in NYHA function class II, 4.0+/-0.3 SEM pg/ml in 16 patients in NYHA function class III, and 5.3+/-0.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.001 vs NYHA function class II). IL-6 plasma levels were 3.1+/-0.6 SEM pg/ml in 38 patients in NYHA function class II, 5.2+/-0.8 SEM pg/ml in 16 patients in NYHA function class III, and 13.3+/-3.9 SEM pg/ml in 11 patients in NYHA function class IV (p < 0.0001 vs NYHA function class II andp < 0.0001 vs NYHA class III). Thus both cytokines increased with increasing severity of heart failure, but only IL-6 plasma levels were different in patients in the more severe function classes. TNF-alpha correlated closely with TNF soluble receptor II (r = 0.8, p < 0.0001) and modestly with serum creatinine (r = 0.6, p < 0.0001), whereas IL-6 plasma levels were not statistically related to kidney function. Significant modest correlations were also found among TNF-alpha and IL-6 (r = 0.3, p < 0.01), big endothelin (r = 0.3, p < 0.01), and noradrenaline levels (r = 0.4, <0.001). This study supports the hypothesis that in heart failure both cytokines, TNF-alpha, and IL-6, as well as neurohumoral factors, play a role in the clinical progression of the disease. Thereby levels of TNF-alpha but not IL-6 seem to be related to concomitant kidney dysfunction.
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PMID:Circulating tumor necrosis factor-alpha levels in chronic heart failure: relation to its soluble receptor II, interleukin-6, and neurohumoral variables. 958 80

1. The release of cytokines following administration of endotoxin and the contribution of nitric oxide (NO) to the subsequent haemodynamic profile were investigated in the conscious mouse. 2. Administration of endotoxin (E. Coli, 026:B6, 12.5 mg kg(-1), i.v.) elevated the concentration of tumour necrosis factor-alpha (TNF-alpha) in the plasma within 0.5 h, reaching a maximum at 2 h and returning to control concentrations by 4 h. In addition, the concentration of interleukin-6 (IL-6) in the plasma was also elevated within 1 h, reaching a maximum at 3 h and remaining elevated throughout the 12 h of study. 3. Endotoxin (12.5 mg kg(-1), i.v.) induced the expression of a Ca2+-independent (inducible) NO synthase in the mouse heart and elevated the concentrations of nitrite and nitrate in the plasma within 4 h, reaching a maximum at 12 h. This was accompanied by a progressive fall in blood pressure over the same period. 4. The vasopressor effect of noradrenaline (0.5-4 microg kg(-1) min(-1), i.v.) administered as a continuous infusion was significantly attenuated 7 h after endotoxin (12.5 mg kg(-1), i.v). 5. The NO synthase inhibitor NG-monomethyl-L-arginine HCl (L-NMMA; 1-10 mg kg(-1), i.v. bolus) reversed the fall in blood pressure when administered 7 h after endotoxin (12.5 mg kg(-1), i.v.). 6. In an attempt to maintain a constant blood concentration, L-NMMA was administered as a continuous infusion (10 mg kg(-1) h(-1), i.v.), beginning 4 h after a lower dose of endotoxin (6 mg kg(-1), i.v.). Such treatment prevented the fall in blood pressure and the elevation of nitrite and nitrate in the plasma throughout the 18 h of observation. 7. The fall in blood pressure following endotoxin (3 mg kg(-1), i.v.) was significantly reduced throughout the 18 h of observation in homozygous mutant mice lacking the inducible NO synthase. 8. In summary, we have developed a model of endotoxin shock in the conscious mouse in which an overproduction of NO by the inducible NO synthase is associated with the haemodynamic disturbances. This model, which exhibits many of the characteristics of septic shock in man, will enable the study of the pathology of this condition in more detail and aid the investigation of potential therapeutic agents both as prophylactics and, more importantly, as treatments.
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PMID:Nitric oxide and the haemodynamic profile of endotoxin shock in the conscious mouse. 964 79

In the thymus, sympathetic nerves run in septa in close connection to subcapsular/perivascular thymic epithelial cells (TEC). Since TEC are supposed to create a microenvironment of cytokines necessary for the development of thymocytes to T cells, we investigated the influence of sympathetic transmitters and co-transmitters on interleukin-6 (IL-6) synthesis in cultivated rat TEC that express markers of perivascular/subcapsular TEC. Noradrenaline and ATP stimulated IL-6 production in the culture supernatants 14- and 23-fold over basal values after 24 h. Co-stimulation with noradrenaline and ATP yielded an additive effect. Synthesis of IL-6 was concentration-dependent upon ATP and appeared to be mediated by P2 purinoceptors. During 24 h stimulation with 1 mM ATP, two thirds of the ligand was degraded mainly to ADP, production of AMP and adenosine was minor or negligible. Thus, in TEC, transmitters and co-transmitters of the sympathetic nervous system have a co-stimulatory effect on synthesis of IL-6 that is an important factor for thymocyte differentiation and proliferation.
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PMID:Effect of transmitters and co-transmitters of the sympathetic nervous system on interleukin-6 synthesis in thymic epithelial cells. 987 34

Reports on patients with hemiparalysis indicate the importance of the nervous system for the pathophysiology of rheumatoid arthritis (RA) or osteoarthritis (OA). Norepinephrine (NE) and opioids seem to be more antiinflammatory neurotransmitters whereas substance P is proinflammatory. The study aimed to investigate the direct noradrenergic nerve-immune cell interaction in human synovial membrane. We used a recently developed superfusion technique with electrical stimulation of synovial membrane to elicit local NE from synovial membrane slices. The readout parameter of synovial immune cells was interleukin-6 (IL-6). IL-6 was spontaneously secreted from RA and OA synovial membranes. Electrical field stimulation intensively reduced IL-6 secretion. In patients with OA or RA, this electrically induced reduction of IL-6 secretion was not significantly changed by alpha- or beta-adrenergic antagonists. The study demonstrates that local endogenous NE seem to play a minor role, which may be due to a depletion of NE or loss of noradrenergic fibers during chronic RA and OA.
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PMID:In vitro superfusion method to study nerve-immune cell interactions in human synovial membrane in long-standing rheumatoid arthritis or osteoarthritis. 1041 20

Changes in circulating levels of catecholamines, cortisol, glucose, interleukin-6 and C-reactive protein and in the leucocyte count were investigated for 7 days after surgery in 158 patients undergoing hip or knee arthroplasty. We compared the responses to the two operations, and also examined the effects of pathology (osteoarthritis and rheumatoid arthritis) on the changes associated with knee arthroplasty. Exploratory factor analysis was applied to the data to identify the variables and sampling times that could be used in future to provide a concise description of the response. Patients undergoing knee arthroplasty showed significantly greater changes in noradrenaline, adrenaline and glucose levels, but not in cortisol levels, compared with those undergoing hip arthroplasty. Interleukin-6 and C-reactive protein concentrations were also significantly greater in knee patients than hip patients; however, when corrected for pathology, many of these differences were not significant. Minimal effects of pathology (chronic inflammation with rheumatoid arthritis) were found on the hormonal changes in knee patients. In particular, there was little evidence to support the inference from animal data that the hypothalamic-pituitary-adrenal axis is impaired. The expected increases in interleukin-6 and C-reactive protein concentrations were found in the rheumatoid arthritis patients. Exploratory factor analysis showed that the response could be separated into six components, accounting for 60% of the total variance, and identified the variables and sampling times indicative of each. In conclusion, there are differences in the hormonal, but not inflammatory, responses to hip and knee arthroplasty. Little evidence was found for an important effect of pathology on the changes associated with knee surgery. Factor analysis provided a useful summary of the data.
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PMID:Hip and knee arthroplasty: a comparison and the endocrine, metabolic and inflammatory responses. 1060 Jun 61

There are some reports that catecholamines may modulate the production of monocytic cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF alpha). The present study was carried out in order to examine the effects of noradrenaline (10(-5), 10(-6) and 10(-7) M), clonidine (10(-5), 10(-6) and 10(-7) M), an alpha2-adrenoceptor agonist, and yohimbine (10(-5), 10(-6) and 10(-7) M), an alpha 2-adrenoceptor antagonist, on the production of IL-6, the IL-1 receptor antagonist (IL-1RA) and TNF alpha by stimulated whole blood of normal humans. We measured the in vitro production of IL-6, TNF alpha and IL-1RA by stimulated (phytohemagglutinin+lipopolysaccharide), diluted whole blood of 16 normal volunteers. The results show that noradrenaline, 10(-5) M, significantly suppressed the production of IL-6; noradrenaline, 10(-5) and 10(-6) M, significantly suppressed the production of IL-1RA and TNF alpha; clonidine, 10(-5) M, significantly suppressed the production of TNF alpha; and yohimbine, 10(-5) and 10(-6) M, significantly suppressed the production of IL-1RA. It is concluded that (1) noradrenaline has significant negative immunoregulatory effects in humans through suppression of the production of (monocytic) proinflammatory cytokines, e.g. IL-6 and TNF alpha, and (2) the suppression of the production of TNF alpha may be related to alpha(2)-adrenoceptor-related mechanisms.
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PMID:The effects of noradrenaline and alpha-2 adrenoceptor agents on the production of monocytic products. 1108 20

The observation that administration of interleukin-1 (IL-1) to animals activates the hypothalamo-pituitary-adrenocortical (HPA) axis stimulated great interest in the significance and mechanism of this response, and in whether other cytokines have similar activities. Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF alpha) share HPA-activating activity, although they are less potent and effective than IL-1, whereas IL-2 and interferon alpha(IFN alpha) lack activity. Small increases in body temperature occur in response to IL-1, IL-6 and TNF alpha, but these changes are prevented by inhibitors of cyclooxygenase (COX) and do not appear to be related to the HPA-activation. The rapid HPA-activating effects of IL-1 are impaired by COX inhibitors, but the more prolonged HPA activation associated with intraperitoneal injections is not affected, indicating multiple mechanisms for IL-1-induced HPA activation. The HPA response to IL-6 is not sensitive to COX inhibitors, but that to TNF alpha appears to be. The HPA-activating activity of IL-1 is associated with increases in the apparent release of brain noradrenaline (NA) and serotonin (5-HT), but not dopamine, as well as with increased brain tryptophan. The NA changes, but not these in serotonin metabolism and tryptophan, are prevented by COX inhibitors. IL-6 has effects on serotonin and tryptophan like those of IL-1, but no detected effect on NA. TNF alpha has some effect on NA and tryptophan, but only at relatively high doses. IFN alpha lacks activity on these neurochemicals. Manipulation of noradrenergic, but not serotonergic systems alters the IL-1-induced HPA activation, suggesting the involvement of NA. However, brain NA does not appear to be essential for HPA activation in mice.
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PMID:Cytokine activation of the HPA axis. 1126 89

Microglial cells rapidly become activated in response to even minor damage of neurons, suggestive of the intimate interactions between neurons and microglial cells. Although mediators for microglia-neuron interactions have not been well identified, neurotransmitters are possible candidates transmitting signals from neurons to microglial cells. Among the neurotransmitters, we focused on the effects of norepinephrine and other adrenergic agonists on the functions of rat cultured microglial cells. Reverse transcriptase polymerase chain reaction studies revealed that microglial cells expressed mRNAs encoding alpha1A, alpha2A, beta1 and beta2 receptors. Norepinephrine and a beta2 adrenergic agonist terbutaline elevated intracellular cAMP level of microglial cells. Norepinephrine, an alpha1 agonist phenylephrine, a beta1 agonist dobutamine and terbutaline suppressed the expressions of mRNAs encoding pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor alpha. Release of tumor necrosis factor alpha and nitric oxide was suppressed by norepinephrine, phenylephrine, dobutamine and terbutaline. An alpha2 agonist clonidine and dobutamine upregulated the expression of mRNA encoding catechol-O-methyl transferase, an important enzyme to degrade norepinephrine. Norepinephrine, dobutamine and terbutaline upregulated the expressions of mRNA encoding 3-phospshoglycerate dehydrogenase, an essential enzyme for synthesis of L-serine and glycine, which are amino acids necessary for neuronal survival. Clonidine upregulated the expression of mRNA encoding an anti-apoptotic factor Bcl-xL. These results suggest that norepinephrine participates in the regulation of brain function at least partly by modulating the functions of microglia.
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PMID:Effects of norepinephrine on rat cultured microglial cells that express alpha1, alpha2, beta1 and beta2 adrenergic receptors. 1242 72

Norepinephrine (NE) is involved in many cardiovascular diseases such as congestive heart failure. We have recently reported that NE had a comitogenic effect in isolated cardiac fibroblasts, and that it activated p42/p44 mitogen activated protein kinase (MAPK). This study was designed to characterize a possible mechanism involved in the proliferative effect of NE. Isolated rat cardiac fibroblasts were exposed to NE (10 microM) for up to 8 h, and interleukin-6 (IL-6) expression was measured by Ribonuclease Protection Assay and Western blotting. The activity of p42/p44MAPK was analyzed by Western blotting. Cell number was assessed by use of a Coulter Counter. IL-6/GAPDH mRNA was increased by NE in a time-dependent manner reaching 23 fold stimulation after 1 h compared to untreated samples. Immunoreactivity to IL-6 was not found in controls. After 16 h of exposure to NE, IL-6 protein was detected. It further increased up to 48 h. The effect of NE on IL-6 mRNA was abolished by the beta-adrenoceptor blockers propranolol, metoprolol (beta1) and ICI 118.551 (beta2), but not by the alpha-adrenoceptor blockers prazosin (alpha1) and yohimbine (alpha2). The MAPK-inhibitor PD98059 suppressed the NE-induced MAPK activation in a concentration-dependent fashion after 5 min, attenuated the NE-induced IL-6 expression after 2 h, and suppressed the proliferative effect of NE from 53 to 18% after 48 h. Recombinant IL-6 caused an increase in proliferation by 31% after 48 h. Simultaneous application of the IL-6 antibody reduced the NE-induced proliferation to 34%, and completely prevented the IL-6 induced effect. These results suggest that NE induces proliferation of rat cardiac fibroblasts in part by increasing the expression of IL-6 through regulation of MAPK.
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PMID:Regulation of norepinephrine-induced proliferation in cardiac fibroblasts by interleukin-6 and p42/p44 mitogen activated protein kinase. 1261 90

Factors which regulate expression of the haptoglobin (acute phase reactant) gene in adipocytes have been examined using 3T3-L1 cells. Haptoglobin expression was observed by Northern blotting in each of the major white adipose tissue depots of mice (epididymal, subcutaneous, mesenteric, and perirenal) and in interscapular brown fat. Expression occurred in mature adipocytes, but not in the stromal-vascular fraction. In 3T3-L1 cells, haptoglobin mRNA was detected from day 4 after the induction of differentiation into adipocytes. Lipopolysaccharide and the cytokines, TNFalpha and interleukin-6, resulted in substantial increases in haptoglobin mRNA in 3T3-L1 adipocytes; the increase (7-fold) was highest with TNFalpha. Increases in haptoglobin mRNA level were also induced by dexamethasone, noradrenaline, isoprenaline, and a beta3-adrenoceptor agonist. In contrast, haptoglobin mRNA was reduced by nicotinic acid and the PPARgamma agonist, rosiglitazone. RT-PCR showed that the haptoglobin gene was expressed in human adipose tissue (subcutaneous, omental). It is concluded that haptoglobin gene expression in adipocytes is stimulated by inflammatory cytokines, glucocorticoids, and the sympathetic system, while activation of the PPARgamma nuclear receptor is strongly inhibitory.
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PMID:Regulation of haptoglobin gene expression in 3T3-L1 adipocytes by cytokines, catecholamines, and PPARgamma. 1469 47


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