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)

Due to the stress imposed by the process of bone marrow transplantation (BMT), we hypothesized that individuals receiving such a transplant underwent an acute phase response (APR). Circulating levels of C-reactive protein (CRP), haptoglobin (HAP), alpha-1 acid glycoprotein (AAG), ceruloplasmin (CER), zinc (Zn), copper (Cu), interleukin-6 (IL-6), albumin (ALB), and thyroxine-binding prealbumin (TBPA), were measured at baseline (Day -7), Day -4, Day 0 (Transplant Day), Day +2, +7, and weekly until day 28 in 14 adults receiving an autologous bone marrow transplant as Phase 1 treatment for various hematologic or solid tumor malignancies. Ten of 14 recipients survived, 9 of which had a significant increase in CRP (p = 0.012), HAP (p = 0.011), AAG (p = 0.002), and decrease in ALB (p = 0.002) and TBPA (p = 0.004) on Day +7, but not Day 0, after bone marrow reinfusion. These findings document the presence of an APR and suggest that the bone marrow transplant process (post reinfusion) initiates a stress response in the recipient.
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PMID:The acute phase response in autologous bone marrow transplantation. 147 99

Stimulation of the immune system results in a series of metabolic changes that are antagonistic toward growth. Monokines, including interleukin-1, tumor necrosis factor, and interleukin-6, are released from cells of the monocyte-macrophage lineage after recognition of immunogens. They appear to mediate homeorhetic response, which alters the partitioning of dietary nutrients away from growth and skeletal muscle accretion in favor of metabolic processes which support the immune response and disease resistance. These alterations include 1) decreased skeletal muscle accretion due to increased rates of protein degradation and decreased protein synthesis; 2) increased basal metabolic rate resulting in increased energy utilization; 3) use of dietary amino acids for gluconeogenesis and as an energy source instead of for muscle protein accretion; 4) synthesis by the liver of acute phase proteins; 5) redistribution of iron, zinc, and copper within the body due to the hepatic synthesis of metallothionein, ferritin, and ceruloplasmin; (6) impaired accretion of cartilage and bone; and 7) release of hormones such as insulin, glucagon, and corticosterone. These monokines also influence the differentiation of cells. Tumor necrosis factor suppresses the differentiation of myoblasts and adipocytes whereas the chicken monokine myelomonocytic growth factor induces the differentiation of granulocytes.
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PMID:Monokines in growth and development. 171 68

It is now generally recognized that interleukin-6 (IL6) is one of the cytokines that mediate the various nonspecific host defense responses to infectious pathogens. Among its now well-demonstrated effects on systemic administration are fever and acute-phase proteinemia. These effects are also activated by the cytokine, IL1, and it has been shown that they are modulated in the preoptic-anterior hypothalamus (POA). This study was undertaken to determine whether this brain region similarly drives the febrile and proteinemic responses to IL6. We compared, therefore, these responses of conscious guinea pigs to human recombinant (hr)IL6 administered intravenously (IV) and into the POA. hrIL6 given IV was not pyrogenic at 1 microgram/kg, caused low-grade, dose-independent fevers (0.4 +/- 0.1 degree C) at 5-20 micrograms/kg, and dose-related fevers at 50 and 100 micrograms/kg (0.6 +/- 0.0 and 0.9 +/- 0.1 degree C, respectively). However, all doses of hrIL6 induced elevations in the plasma levels of ceruloplasmin (as an indicator of acute-phase proteins), albeit not in a dose-dependent manner. Indomethacin (10 mg/kg, injected intramuscularly 20 min before hrIL6) abolished the febrile response, but did not prevent the rise in plasma ceruloplasmin levels. Fever and ceruloplasminemia were also evoked by 50 and 100 ng of hrIL6 injected into the POA (1 microliter bilaterally), but not by 25 ng. These results indicate that the inductions of fever and plasma ceruloplasmin by IL6 are, like those of IL1, modulated in the POA, albeit the effective doses are much higher than those of IL1.
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PMID:Neuromodulation of acute-phase responses to interleukin-6 in guinea pigs. 212 80

The synthesis of all the major acute phase plasma proteins is stimulated in rat hepatoma and primary cultures of hepatocytes by three, structurally and functionally distinct groups of hormones: 1) hepatocyte-stimulating factors (HSF) and interleukin-6 (IL-6); 2) interleukin-1 (IL-1) and tumor necrosis factor (TNF); and 3) glucocorticoids. Each plasma protein gene requires a specific combination of these 3 hormone types for maximal expression. One set of acute phase proteins, including alpha 2-macroglobulin, alpha 1-antichymotrypsin ( = contrapsin), cysteine protease inhibitor ( = thiostatin), alpha 1-antitrypsin, ceruloplasmin and fibrinogens are predominantly regulated by the keratinocyte-derived HSF-III/-II or IL-6, while a second set of proteins, including alpha 1-acid glycoprotein (AGP), haptoglobin and complement C3 are predominantly regulated by keratinocyte-derived HSF-I, IL-1 or TNF. In conjunction with the above peptide hormones, glucocorticoids synergistically enhance the stimulated expression of most, but not all, acute phase proteins. An exceptionally strong synergy between HSF (or IL-6), IL-1 and glucocorticoids is noted for the activation of the AGP gene. To elucidate the molecular mechanisms of regulation, we have identified the cis-acting genetic elements through which all these hormones control the transcriptional activity of the AGP gene. It appears that acute phase activates a specific nuclear binding protein in the rat liver that interacts with the peptide hormone responsive element located 5 kb upstream of the transcriptional start site.
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PMID:Regulation of acute phase protein genes by hepatocyte-stimulating factors, monokines and glucocorticoids. 248 67

Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.
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PMID:Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate--the marmoset. 751 39

Serum levels of alpha 1-antichymotrypsin (alpha 1-ACT) were measured in patients with early and late onset Alzheimer's disease (e-AD, 1-AD), patients with vascular dementia (VD) and healthy elderly. Patients with 1-AD were divided into two groups, one had normal alpha 1-ACT values and one had increased serum levels of alpha 1-ACT. Other acute phase proteins were also measured. The serum levels of alpha 2-macroglobulin (alpha 2-MG), alpha 1-antitrypsin (alpha 1-AT), ceruloplasmin (CER), transferrin (TRSF) and alpha 1-acid glycoprotein (alpha 1-ac.GL) were within the normal range. The C reactive protein (CRP) was occasionally detectable at low concentrations in e-AD, in both groups of 1-AD patients and in VD patients. Low serum concentrations of interleukin-6 (IL-6) were found in a higher proportion of 1-AD than in patients with e-AD or VD. These results indicated that increased levels of alpha 1-ACT along with occasional detection of IL-6 might be peripheral markers of the 'acute reaction' in the brain.
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PMID:Increased serum alpha 1-antichymotrypsin in patients with probable Alzheimer's disease: an acute phase reactant without the peripheral acute phase response. 753 91

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

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

The acute phase response (APR) that follows injury or infection is characterized by a decrease in serum zinc concentrations, which we hypothesized benefits the host. Additionally, we proposed that preventing this decline by supplementing zinc would result in an exaggerated APR as indicated by elevated temperatures, increased serum cytokine concentrations, interleukin 6 and the acute phase protein (ceruloplasmin). A prospective, randomized, double-blinded, clinical trial was conducted. Patients on home parenteral nutrition with a diagnosis of catheter sepsis and patients with a diagnosis of pancreatitis, also on total parenteral nutrition (TPN), were recruited for the study. Following enrollment, block randomization was used to assign patients to receive 0 mg (n = 23) or 30 mg (n = 21) of zinc per day for the first 3 d of TPN. Blood samples for measurement of serum zinc, copper, ceruloplasmin and interleukin-6 were obtained upon enrollment and on d 1 through 3 of TPN. The highest temperatures reported on these days in the medical record were also recorded. Repeated measures ANOVA was used to determine differences in the primary outcome variables over time. No significant differences between groups were observed in serum interleukin-6 or ceruloplasmin concentrations. A significantly higher (P = 0.035) temperature was observed in the zinc-supplemented group compared with the control group on d 3 of parenteral nutrition. We conclude that parenteral zinc supplementation in patients experiencing a mild APR resulted in an exaggerated APR as evidenced by a significantly higher febrile response.
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PMID:Parenteral zinc supplementation in adult humans during the acute phase response increases the febrile response. 904 May 47

Particulate air pollution causes increased cardiopulmonary morbidity and mortality, but the chemical determinants responsible for its biologic effects are not understood. We studied the effect of total suspended particulates collected in Provo, Utah, an area where an increase in respiratory symptoms in relation to levels of particulate pollution has been well documented. Provo particulates caused cytokine-induced neutrophil chemoattractant-dependent inflammation of rat lungs. Provo particulates stimulated interleukin-6 (IL-6) and IL-8 production, increased IL-8 messenger RNA (mRNA) and enhanced expression of intercellular adhesion molecule-1 (ICAM-1) in cultured BEAS-2B cells, and stimulated IL-8 secretion in primary cultures of human bronchial epithelium. Cytokine secretion was preceded by activation of the transcription factor nuclear factor-kappaB (NF-kappaB) and was reduced by treatment of cultures with superoxide dismutase, deferoxamine, or N-acetylcysteine. These biologic effects were replicated by culturing BEAS cells with quantities of Cu2+ found in Provo extract. IL-8 secretion by BEAS cells could be modified by addition of normal constituents of airway lining fluid to the culture medium. Mucin significantly reduced IL-8 secretion, and ceruloplasmin significantly increased IL-8 secretion and activation of NF-kappaB. These findings suggest that copper ions may cause some of the biologic effects of inhaled particulate air pollution in the Provo region of the United States, and may provide an explanation for the sensitivity of asthmatic individuals to Provo particulates that has been observed in epidemiologic studies.
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PMID:Copper-dependent inflammation and nuclear factor-kappaB activation by particulate air pollution. 973 Aug 64


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