UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic zinc uptake and accumulation were compared in freshly isolated and cultured hepatocytes prepared from control (MT+/+) and metallothionein (MT)-null (MT-/-) mice. In freshly isolated hepatocytes, rapid (10-15 min) exchange of 65Zn was proportional to the Zn concentration in the medium and occurred to the same extent in hepatocytes from MT+/+ and MT-/- mice. In 24 h culture experiments with MT+/+ and MT-/- hepatocytes it was shown that approx. 40% of newly acquired cell-associated Zn was attached to the cell surface and not internalized. In MT+/+ and MT-/- hepatocyte cultures, internalized Zn (intZn) increased in proportion to extracellular Zn. Zn accumulation in MT-/- hepatocytes was only 60% that of MT+/+ cells. Addition of 1 microM dexamethasone (Dex) and recombinant mouse interleukin-6 (IL-6; 100 units/ml) increased MT accumulation by 8.6-fold in MT+/+ hepatocytes (at 50 microM Zn) and there was an associated parallel increase in intZn. Dex and IL-6 did not increase intZn in the MT-/- hepatocytes. At 16 h after an intraperitoneal injection of 5 micrograms/g Zn, plasma and urine Zn concentrations were 69 +/- 10 microM and 86 +/- 25 microM respectively in MT-/- mice (n = 10) and 27 +/- 1 microM and 23 +/- 4 microM respectively in MT+/+ controls (n = 9) (P < 0.001, plasma; P < 0.05, urine). Hepatic cytosolic Zn concentrations doubled in MT+/+ mice and increased by a significant 15% in MT-/- mice. There was no increase in hepatic Zn (dry wt.) concentrations or in total hepatic Zn, demonstrating that the increase in cytosolic Zn in MT-/- mice was due to hepatic water loss rather than net Zn uptake. It appears that even at extreme plasma concentrations of Zn, little if any accumulates within the liver when there is no MT available for its sequestration. That this is not fully demonstrated in vitro is probably due to nature of cell culture, where organ architecture is lost and the external protein binding milieu is less complex.
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PMID:Hepatic zinc in metallothionein-null mice following zinc challenge: in vivo and in vitro studies. 761 65

Zinquin [ethyl (2-methyl-8-p-toluenesulphonamido-6-quinolyloxy)acetate], a new intracellular zinc fluorophore, was used to reveal and to measure Zn in cultured rat hepatocytes before and after metallothionein (MT) induction. Hepatocytes labelled with an intense extranuclear fluorescence. Culture with combinations of Zn, dexamethasone and interleukin-6, increased intracellular MT by 24-fold, Zn 3-fold, and Zinquin fluorescence by approx. 2-fold above control values. Zinquin fluorescence correlated in descending order with the total cellular Zn (r = 0.747), exchangeable Zn (r = 0.735), soluble cytosolic Zn (r = 0.669) and MT (r = 0.666). When Zinquin was incubated with a cytosolic fraction of liver proteins before Sephadex G-75 column chromatography, it fluoresced with free, MT-incorporated and protein-bound Zn. Although only a slight attenuation of fluorescence was seen with high-molecular-mass protein-bound Zn, MT was degraded by 60% in the presence of Zinquin. The undegraded Zn-MT fluoresced at about 20% of the expected intensity. Although Zinquin fluoresces with all cytosolic Zn, caution is required when comparisons are made between samples with different concentrations of MT. This limitation was demonstrated by staining liver slices from adjuvant-treated rats where MT was increased 24-fold, intracellular Zn by 77%, but Zinquin fluorescence by only 19% above controls. Nevertheless, Zinquin should prove to be a useful tool for studying the distribution of Zn in living cells.
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PMID:Measurement of zinc in hepatocytes by using a fluorescent probe, zinquin: relationship to metallothionein and intracellular zinc. 798 Apr 47

The intracellular signals induced by IL-1 and IL-6 have been described but there are few details of the signals they induce in liver-derived cells during initiation of acute phase protein synthesis. We therefore used an in vitro system to investigate signalling by IL-1 and IL-6 in the human liver cell line, HepG2. Chloramphenicol acetyl transferase (CAT) expression vectors, under the control of activator protein-1 (pTRE-CAT), nuclear factor kappa B (pNF-CAT) or no enhancer region (pBLCAT2), were transfected into HepG2 cells and the effects of the cytokines on their activity was studied. Profound changes in liver processing of heavy metals and the induction of metal-dependent acute proteins are also seen during the acute phase response. To determine if the supply of metal ions could itself influence signalling we also investigated the effects of cadmium and zinc on the activity of the transfected vectors. Both alpha and beta forms of interleukin-1 increased the expression of pTRE-CAT and pNF-CAT, but not pBLCAT2, while interleukin-6 had no effect, suggesting that activator protein-1 and nuclear factor kappa B activity was induced by interleukin-1, but not interleukin-6. Specificity of the effect of interleukin-1 alpha was confirmed using an anti-interleukin-1 alpha monoclonal antibody. Zinc and cadmium also increased pTRE-CAT expression, but not pNF-CAT or pBLCAT2. Removal of heavy metal ions from the culture medium resulted in decreased pTRE-CAT expression, while pNF-CAT and pBLCAT2 were relatively unaffected, confirming the stimulatory effect of metals on activator protein-1, but not nuclear protein kappa B activity. Therefore, metal and interleukin-1-mediated signal transduction may involve overlapping pathways, whereas interleukin-1 and interleukin-6 act via different pathways in liver cells.
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PMID:Control of activator protein-1 and nuclear factor kappa B activity by interleukin-1, interleukin-6 and metals in HEPG2 cells. 803 60

Metallothionein (MT) synthesis induced by the inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF), was studied in vivo. Administration of recombinant human IL-6 or TNF to rats caused the acute phase responses including rapid decreases in plasma zinc (Zn), and increases in plasma copper (Cu) and ceruloplasmin. Hepatic concentration of MT-I, one of MT isoforms, began to increase within 3 h after the injection of IL-6 or TNF. In IL-6-treated rats, MT-I concentration in liver reached a maximum level at 12 h and decreased with a transient rebound, whereas, in TNF-treated rats, a high level of MT-I lasted for about 48 h. MT-II, the other MT isoform, was induced more than MT-I in liver by both cytokines. MT-I was also induced in lung and heart by TNF, but little by IL-6. The data suggest that IL-6 may be responsible for MT synthesis in liver, whereas TNF may be responsible not only in liver but also in lung and heart. Furthermore plasma concentration of MT did not always reflect the enhanced concentration of MT by TNF and IL-6 in liver, suggesting involvement of many factors influencing plasma MT levels. The interrelation between IL-6 and TNF for MT synthesis has also been discussed.
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PMID:Differential induction of metallothionein synthesis by interleukin-6 and tumor necrosis factor-alpha in rat tissues. 818 7

Metallothionein induction was investigated using vascular endothelial cells derived from bovine aorta in a culture system. The induction occurred by cadmium (2 and 5 microM) but not by zinc (10 and 300 microM) after a 24-h incubation of the confluent cultures. It was revealed that cytokines including interleukin-1 beta, interleukin-6, tumor necrosis factor alpha and transforming growth factor beta (1 ng/ml each) have a capacity of metallothionein induction. In these inducers, only cadmium and tumor necrosis factor alpha exhibited significant cytotoxicity, suggesting that metallothionein is not induced simply in response to cytotoxicity. It was found that either thrombin or endothelin-1 which are coagulation factor or anti-fibrinolytic factor, respectively, also induced metallothionein synthesis. It was therefore suggested that metallothionein in endothelial cells may be involved in the regulation of the functions of these cells as well as the protection against cytotoxic agents.
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PMID:Metallothionein induction by cadmium, cytokines, thrombin and endothelin-1 in cultured vascular endothelial cells. 841 75

Metal fume fever is a flulike illness caused by zinc oxide inhalation and accompanied by an impressive pulmonary cellular response. We hypothesized that the syndrome is mediated by cytokines released in the lung after exposure to zinc oxide fume. We carried out 26 experimental welding exposures in 23 volunteer subjects, performing postexposure bronchoalveolar lavage (BAL) 3 h (n = 6), 8 h (n = 11), or 22 h (n = 9) after exposure. We detected tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-8 (IL-8) varying in a time- and exposure-related manner. The concentration of TNF in the BAL fluid supernatant was significantly greater at 3 h than at 8 h or 22 h after exposure (p < 0.05), exhibiting a statistically significant exposure-response relationship to airborne zinc at each follow-up time period (p < 0.05). TNF concentrations were statistically correlated with those of IL-6 in BAL supernatant obtained at 22 h (r = 0.78, p = 0.01) and with concentrations of IL-8 in BAL 8 h after exposure (r = 0.85, p = 0.001). IL-6 displayed a significant exposure-response relationship to zinc (p < 0.05) at 22 h. IL-8 exhibited a significant exposure-response relationship to zinc (p < 0.05) at 8 h after exposure, a time at which IL-8 correlated with marked increases in BAL fluid polymorphonuclear leukocytes (PMN) (r = 0.7, p = 0.01). Although we also detected interleukin-1 (IL-1) in BAL samples, this cytokine did not demonstrate a statistically significant exposure response. TNF, IL-6, and IL-8 in BAL fluid supernatant concentrations increased in a time and exposure-dependent fashion after zinc oxide welding fume exposure. The time course of increased cytokines, their correlations with one another and with PMN in the BAL fluid, and the consistency of our findings with the known kinetics and actions of these cytokines support the hypothesis that a network of cytokines is involved in the pathogenesis of metal fume fever.
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PMID:Cytokines in metal fume fever. 842 Apr 6

The comparative influence of dietary zinc status and recombinant human interleukin-1 alpha (rhIL-1 alpha) and recombinant human interleukin-6 (rhIL-6) on metallothionein (MT) gene expression was examined in rat bone marrow and liver. Growing male rats were fed a diet with 5 (restricted), 30 (control), or 180 (supplemented) mg Zn/kg for 14 d. On d 15, rats were injected with 5 micrograms of rhIL-1 alpha or rhIL-6. Marrow metallothionein responded directly to dietary zinc but did not respond to these cytokines. Significantly less zinc accumulated in marrow from the zinc-restricted rats compared with control or supplemented rats. Analysis of metallothionein isoform mRNA expression showed MT-1 is the primary gene expressed in marrow. A significant interaction between dietary zinc and cytokine treatment was observed in the liver. Hepatic metallothionein induction following both rhIL-1 alpha and rhIL-6 injection was directly related to dietary zinc intake. Expression of hepatic metallothionein isoform mRNAs suggested MT-1 responded to zinc and MT-2 responded to cytokines. These results indicate that metallothionein gene expression in both the marrow and the liver responds to dietary zinc status. In contrast, liver metallothionein expression can be altered by these cytokines, which are known to act on many cell types. Furthermore, these results suggest that bone marrow metallothionein could be of importance in the development of marrow cells.
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PMID:Metallothionein expression in rat bone marrow is dependent on dietary zinc but not dependent on interleukin-1 or interleukin-6. 846 65

We investigated the reciprocal effects of interleukin-6 (IL-6), glucocorticoid and zinc (Zn) on metallothionein (MT) synthesis in rats. MT synthesis in the liver, which is a key responsible organ in acute phase responses, was induced by IL-6 or dexamethasone (Dex), and in an additive manner by a combination of IL-6 and Dex 18 h after injection. MT synthesis in the lung and heart was evaluated by immunoassay using a specific antibody to MT-1, because of its low concentration in these tissues. Heart concentrations of MT-1 were significantly increased by IL-6, and were further increased by the combination of IL-6 and Dex, although Dex by itself had no effect. This suggests a synergistic effect of IL-6 and Dex on MT-I synthesis in the heart. A similar synergism was observed in the lung. To study the effect of Zn on the induction of MT and acute phase proteins, Zn, IL-6 and Dex were administered in various concentrations. The increase in liver MT induced by the combination of IL-6 and Dex with Zn (130 micrograms MT/g of liver) was greater than the sum of the increases induced by (IL-6 + Zn) and by (Dex + Zn) (103 micrograms MT/g), suggesting a synergistic increase. The data indicate that the maximal increase in the induction of MT by a combination of IL-6 and Dex depends on an adequate liver Zn content. Thus, the in vivo synergistic induction of acute phase proteins by IL-6, glucocorticoid and Zn may be required for the maximal and rapid response, not only in liver but also in other tissues including heart and lung. This suggests that the synergistic reaction may be important for an enhancement of the radical scavenging ability of tissues in acute phase responses.
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PMID:Synergistic induction of metallothionein synthesis by interleukin-6, dexamethasone and zinc in the rat. 879 67

This study examined muscle swelling and changes in inflammatory markers in the blood following eccentric exercise-induced muscle damage. Subjects (N = 14) who had not been involved in a resistance training program performed 24 maximal eccentric actions of the elbow flexors. Muscle swelling was assessed by measures of the upper arm circumference (CIR), ultrasonography (USG), and magnetic resonance imaging (MRI). Plasma concentrations of interleukin-1 alpha, interleukin-1 beta, interleukin-2, interleukin-6, tumor necrosis factor-alpha, and plasma levels of C-reactive protein, cortisol, and zinc were analyzed. Established indicators of muscle damage (maximal isometric force, range of motion, muscle soreness, and plasma creatine kinase, aspartate aminotransferase, and lactate dehydrogenase activities) were also measured. All measures, including CIR and USG, except for MRI, were assessed immediately before and after and for 5 d post-exercise. MRI was taken at pre- and 1, 3, 6, 10, 23, 31, and 58 d post-exercise. All muscle damage indicators changed significantly after exercise. A large increase in CIR (> 20 mm) was found 4-5 d after exercise, and this coincided with USG, showing an increase in muscle thickness. The echointensity of USG increased with the enlargement of the elbow flexors. MRI displayed enlargement of the biceps brachii and brachialis cross-sectional area that started at 1 d, and lasted until 23 d, post-exercise. The most profound increase in the enlargement and signal intensity of the MRI was found 3 or 6 d after exercise. However, none of the plasma levels of inflammatory makers showed significant muscle swelling, which is indicative of muscle edema, but the inflammatory responses after exercise appear to be different from those accompanying infection or tissue injury.
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PMID:Changes in indicators of inflammation after eccentric exercise of the elbow flexors. 887 3

The manipulation of stress gene expression by heavy metals provides protection against the lethal effects of endotoxemia in murine models of septic shock. Recent in vitro studies with alveolar macrophages or monocytes show that induction of the stress response in these cells is followed by a decreased liberation of major cytokines [tumor necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-1)] after endotoxin challenge. These findings suggest that the increased resistance to endotoxin in vivo after stress protein induction could be explained by an altered pattern of inflammatory mediator release. Therefore, we measured the time course of thromboxane-B2 (TxB2), 6-keto-PGF1 alpha, platelet activating factor (PAF), TNF alpha, interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) formation with and without induction of the stress response in an established porcine model of recurrent endotoxemia (Klosterhalfen et al., Biochem Pharmacol 43: 2103-2109, 1992). Induction of the stress response was done by a pretreatment with Zn2+ (25 mg/kg zinc-bis-(DL-hydrogenasparate = 5 mg/kg Zn2+). Pretreatment with Zn2+ prior to lipopolysaccharide (LPS) infusion induced an increased heat shock protein 70 and metallothionein expression in the lungs, liver, and kidneys and increased plasma levels of TNF alpha, IL-1 beta, IL-6, and TxB2 as opposed to untreated controls. After LPS infusion, however, pretreated animals showed significantly decreased peak plasma levels of all mediators as opposed to the untreated group. The time course of mediator release was identical with the decreasing and increasing three peak profiles described previously. Hemodynamic data presented significantly decreased peak pulmonary artery pressures and significantly altered hypodynamic/hyperdynamic cardiac output levels in the pretreated group. In conclusion, the data show that the induction of stress proteins by Zn2+ could be a practicable strategy to prevent sepsis.
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PMID:Influence of heat shock protein 70 and metallothionein induction by zinc-bis-(DL-hydrogenaspartate) on the release of inflammatory mediators in a porcine model of recurrent endotoxemia. 893 27

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