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)

Previous work showed that mice treated with platelet-specific antiserum prior to whole-body irradiation did not suffer the degree or duration of thrombocytopenia as did irradiated control mice. We now report that a partially purified preparation of a thrombocytopoiesis-stimulating factor (TSF or thrombopoietin) mimics the biological effects of platelet-specific antiserum treatment in hematopoietically suppressed mice. Male C3H mice were exposed to 3.0 or 4.5 Gy of 137Cs gamma radiation and injected with a total dose of 4 units (U) of TSF. Human serum albumin (HSA) and rabbit anti-mouse platelet serum-injected mice, along with unirradiated mice, served as controls. Packed cell volumes (PCV), RBC counts, WBC counts, platelet counts, and percentage 35S incorporation into platelets were measured in mice at various days (7-14) following treatment. The results showed that irradiated mice treated with TSF had increased 35S uptake into platelets and higher platelet counts than HSA-treated controls. Also, PCV, RBC counts, and WBC counts of irradiated mice treated with TSF were significantly higher than values for HSA-treated mice. Additional experiments using 40,000 U/mouse of Interleukin-6 (IL-6), 227 U/mouse of granulocyte macrophage-colony stimulating factor (GM-CSF), or a combination of GM-CSF and IL-6 did not show increased platelet counts or 35S incorporation into platelets on Days 10 and 14 when compared to other mice treated with control substances. These results suggest that the radioprotective effects of platelet antibodies reported previously may be due to the release and action of thrombopoietin. These studies also demonstrate that thrombopoietin therapy will modulate the severe thrombocytopenia that occurs in radiation-induced bone marrow suppression.
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PMID:Thrombopoietin from human embryonic kidney cells causes increased thrombocytopoiesis in sublethally irradiated mice. 141 Feb 78

We have investigated the effect of cytokines, including interleukin-6 (Il-6), interleukin-1 alpha (Il-1 alpha), and tumor necrosis factor-alpha (TNF-alpha), on the inducible expression of cytochrome P450s (CYP) CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. The ability of these cultures to mimic the acute phase response when stimulated with cytokines was evaluated using immunoblotting to measure the production of albumin, ferritin, fibrinogen, and ceruloplasmin. The cytokines exhibited specific patterns of action on the production of these proteins. Albumin was depressed by all the cytokines. In contrast to Il-6 and Il-1 alpha, TNF-alpha reduced the production of fibrinogen and ceruloplasmin but stimulated the production of ferritin. When cells were treated with the CYP inducer alone, large increases in the expression of CYP1A1 and CYP1A2 by beta-naphthoflavone and of CYP3A4 by rifampicin were observed at messenger RNA (mRNA) and protein levels, by ribonuclease protection and immunoblotting, respectively. When the cells were treated with the inducer plus cytokines, the induction of mRNA was greatly reduced. Again, specific patterns of action were revealed: Il-6 had the most potent effect on CYP3A4, whereas TNF-alpha was the most potent with CYP1A genes. In all cases, changes at the protein levels paralleled changes at the mRNA levels. In cells preinduced with beta-naphthoflavone or rifampicin, the decay with time of the levels of the CYP1A2 or CYP3A4 proteins, after the removal of the inducer, was not affected by cytokines. We conclude that cytokines strongly repress the inducibility of CYP1As and CYP3A4 genes at a transcriptional or a posttranscriptional level, but affect neither the rate of translation of CYP mRNAs nor the rate of degradation of the CYP proteins in these cultures.
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PMID:Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture. 755 64

In situ oestrogen synthesis makes an important contribution to the high oestrogen concentration found in breast tumours. Cytokines, including interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF alpha), have been shown to regulate aromatase activity in fibroblasts derived from normal and malignant breast tissues. In the present study, the ability of other cytokines in the IL-6 superfamily (IL-11 and oncostatin M) to stimulate aromatase activity has been confirmed. Formation of oestrone via the oestrone sulphatase pathway may be the major route of tumour oestrogen synthesis and in the present study TNF alpha was found to stimulate sulphatase activity in a dose-dependent manner. Human serum albumin was also found to be a potent stimulator of oestrone sulphatase activity. Its stimulatory effect was blocked by basic fibroblast growth factor, but not by several other growth factors tested. Insight into the regulation of oestrogen synthesis in breast tumours should enable the development of novel compounds to inhibit oestrogen synthesis in women with breast cancer.
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PMID:Regulation of aromatase and sulphatase in breast tumour cells. 894 89

Two characteristic elements of the acute-phase response are an altered pattern of circulating hepatic proteins and fever. Whereas a fever-induced heat shock response could affect expression of acute-phase proteins in the liver, the effects of a modest temperature increase on protein secretion in interleukin-6 (IL-6)-stimulated HepG2 cells were investigated. The response of HepG2 cells to IL-6 stimulation was significantly affected by heat treatment at 40 degreesC. Albumin secretion rates, which were reduced by a factor of 2 in response to either heat shock or IL-6 stimulation alone, were down-regulated by a factor of 4 when IL-6 was administered simultaneously with a continuous 40 degrees C heat shock. IL-6-induced fibrinogen up-regulation was significantly reduced by heat treatment (P < .01), and secretion rates were indistinguishable from control levels after 2 days (P > .10). Unexpectedly, heat shock at 40 degrees C induced a fivefold up-regulation of haptoglobin production in the absence of IL-6. Simultaneous heat shock and IL-6 stimulation caused a synergistic enhancement of haptoglobin expression, with secretion rates increasing up to 30-fold compared with unstimulated control cells. For all three proteins, the interaction between temperature and IL-6 concentration was statistically significant (P < .001). Heat treatment resulted in significant alterations of both the kinetics and sensitivity of IL-6-induced protein synthesis, suggesting a major modification of the mechanism of acute-phase protein regulation at 40 degreesC. In summary, the data show that heat shock can significantly modulate the pattern of acute-phase protein expression and that fever may be an important regulatory factor in the acute-phase response.
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PMID:Interaction between heat shock and interleukin 6 stimulation in the acute-phase response of human hepatoma (HepG2) cells. 975 36

The acute-phase expression of pig MAP (major acute-phase protein)/ITIH4 (inter-alpha-trypsin inhibitor heavy chain 4) and haptoglobin were analysed in primary cultures of isolated pig hepatocytes in response to recombinant human (rh) cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), interleukin-6 (IL-6), as well as to bacterial lipopolysaccharide (LPS). Analysis of pig MAP/ITIH4 and haptoglobin mRNAs was carried out by RT-PCR amplification. Secreted proteins from the cytokine-treated hepatocytes were quantified by immunochemical techniques. Time-course and dose-response experiments show that pig MAP/ITIH4 and haptoglobin belong to the type II acute-phase proteins, as they are specifically induced by rhIL-6 and not by rhTNF-alpha or rhIL-1. Stimulation of cultured pig hepatocytes with rhIL-6 for 48 h at doses of 1000 U.mL-1 showed a fourfold to fivefold increase in pig MAP/ITIH4 concentration in the medium, while the concentration of haptoglobin only increased twofold. A similar increase in the concentration of pig MAP/ITIH4 was also observed in media of LPS-treated hepatocytes with the simultaneous generation of IL-6 by the Kupffer cells present in the cultures. Albumin secretion decreased after stimulation with doses of 100 or 1000 U.mL-1 rhTNF-alpha, rhIL-1 or rhIL-6. Therefore, it can be concluded that pig MAP/ITIH4 behaves as a major acute-phase protein produced by porcine hepatocytes under the effect of inflammatory cytokines.
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PMID:Pig MAP/ITIH4 and haptoglobin are interleukin-6-dependent acute-phase plasma proteins in porcine primary cultured hepatocytes. 1071 21

The acute effects of active and passive ascent to high altitude on plasma volume (PV) and rates of synthesis of albumin and fibrinogen have been examined. Measurements were made in two groups of healthy volunteers, initially at low altitude (550 m) and again on the day after ascent to high altitude (4,559 m). One group ascended by helicopter (air group, n = 8), whereas the other group climbed (foot group, n = 9), so that the separate contribution of physical exertion to the response could be delineated. PV was measured by dilution of (125)I-labeled albumin, whereas synthesis rates of albumin and fibrinogen were determined from the incorporation of isotope into protein after injection of [ring-(2)H(5)]phenylalanine. In the air group, there was no change in PV at high altitude, whereas, in the foot group, there was a 10% increase in PV (P < 0.01). Albumin synthesis (mg. kg(-1). day(-1)) increased by 13% in the air group (P = 0.058) and by 32% in the foot group (P < 0.001). Fibrinogen synthesis (mg. kg(-1). day(-1)) increased by 40% in the air group (P = 0.068) and by 100% in the foot group (P < 0.001). Hypoxia and alkalosis at high altitude did not differ between the groups. Plasma interleukin-6 was increased modestly in both groups but C-reactive protein was not changed in either group. It is concluded that increases in PV and plasma protein synthesis at high altitude result mainly from the physical exercise associated with climbing. However, a small stimulation of albumin and fibrinogen synthesis may be attributable to hypobaric hypoxia alone.
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PMID:Enhanced synthesis of albumin and fibrinogen at high altitude. 1116 51

The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied. Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture. Intravital video microscopy of cremasteric postcapillary venules was performed. Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice. Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 microm per minute; p < 0.001). Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01). Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin. Survival was significantly improved at 48 hours in mice treated with pentostatin. These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis. Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.
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PMID:Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis. 1209 Nov 65

The diet of industrialised countries is usually rich in amino acids, which are in part used as a source of calories. However, metabolic alterations are observed in diseased patients and a preferential retention of Sulphurated Amino Acids (SAA) occurs during the inflammatory response. Moreover, it has been demonstrated in a model of an acute sepsis phase of rats that the metabolism of Cysteine is modified. The liver converts Cysteine at a different ratio of Sulphate to Taurine (Tau) i.e. the sulphate production decreases while the Tau conversion increases. The Glutathione (GSH) concentration is greater in the liver, kidneys and other organs and the Cysteine incorporation into proteins is higher in the spleen, lungs and plasma (Acute Phase Proteins) while the Albumin level decreases. The pro-inflammatory cytokines such as Interleukin-1, Interleukin-6 and TNF- alpha are the main initiators that alter protein and amino acid metabolism. Another important phenomenon is the impairment of Methionine conversion to Cysteine during stress. For example, premature infants or AIDS patients are capable of synthesizing Cysteine from Methionine at a much lower rate. Thus, the metabolic flow through the trans-sulphuration path may be inadequate to meet the Cysteine demand under critical conditions. In this complex picture, an SAA supply may contribute to an immune system regulation.
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PMID:The regulation of sulphurated amino acid junctions: fact or fiction in the field of inflammation? 1243 3

The effect of mechanical stress generated within a three-dimensional bioreactor on the co-culture of hepatic parenchymal cells (PC) and hepatic nonparenchymal cells (NPC) was assessed to develop a bioartificial liver that can produce factors accelerating liver regeneration. A rotating radial flow bioreactor was used to provide mechanical stress to a co-culture of PC and NPC that were isolated from rats. They were co-cultured in the reactor under static or dynamic conditions. Albumin, interleukin-6 (IL-6), hepatocyte growth factor (HGF), and lactate dehydrogenase (LDH) were measured at intervals. Electron microscopy was also performed. LDH was not significantly different between the static and mechanical stress-loaded cultures, while albumin and interleukin-6 levels were higher in the latter at all sampling times. Only the co-cultures loaded with mechanical stress produced HGF in the early stage of culture (hours 3 and 6). Histologically, the cells retained their structure when cultured under dynamic conditions. These results suggested that an appropriate level of mechanical stress enabled co-cultures of PC and NPC to produce IL-6, HGF, and other factors that accelerate liver regeneration.
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PMID:Effect of mechanical stress imposition on co-culture of hepatic parenchymal and nonparenchymal cells: possibility of stimulating production of regenerating factor. 1596 26

Albumin induces oxidative stress and cytokine production in proximal tubular cells (PTECs). Albumin-bound fatty acids (FAs) enhance tubulopathic effects of albumin in vivo. We proposed that FA aggravation of albumin-induced oxidative stress in PTECs might be involved. We hypothesized that mitochondria could be a source of such stress. Using a fluorescent probe, we compared reactive oxygen species (ROS) production after exposure of PTECs to bovine serum albumin (BSA) alone or loaded with oleic acid (OA-BSA) (3-30 g/l for 2 h). There was no difference in cellular albumin uptake, but OA-BSA dose-dependently induced more ROS than BSA alone (P<0.001). OA-BSA-induced ROS was significantly alleviated by mitochondrial inhibition, but not by inhibitors of nicotinamide adenine dinucleotide phosphate hydrogenase (NADPH) oxidase, xanthine oxidase, or nitric oxide synthase. Gene expression analysis showed that neither the NADPH oxidase component p22phox nor xanthine oxidase was induced by BSA or OA-BSA. OA-BSA, in contrast to BSA, failed to induce mitochondrial manganese superoxide dismutase 2 (SOD2) expression. OA-BSA showed a greater capacity than BSA to downregulate heme oxygenase-1 mRNA expression and accentuate inflammatory cytokine mRNA and protein. Supplementation of SOD activity with EUK-8 reduced ROS, and interleukin-6 protein expression was suppressed by both mitochondrial inhibition and SOD augmentation. Thus, in PTECs, FAs accentuate albumin-induced oxidative stress and inflammatory cytokine expression via increased mitochondrial ROS, while frustrating protective antioxidant responses.
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PMID:Albumin-bound fatty acids induce mitochondrial oxidant stress and impair antioxidant responses in proximal tubular cells. 1683 28


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