UNIPROT:P05231 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

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

A noncovalently bound dimeric form of recombinant human IL-6 interleukin-6 (IL-6D) was shown to be an antagonist for IL-6 activity, in a STAT3 tyrosine phosphorylation assay using HepG2 cells, under conditions where it does not dissociate into monomeric IL-6 (IL-6M). The fluorescence from Trp157, the single tryptophan residue in the primary sequence of IL-6, is altered in IL-6D, where the wavelength maximum is blue-shifted by 3 nm and the emission intensity is reduced by 30%. These data suggest that Trp157 is close to, but not buried by, the dimer interface. Both IL-6D and IL-6M are compact molecules, as determined by sedimentation velocity analysis, and contain essentially identical levels of secondary and tertiary structure, as determined by far- and near-UV CD, respectively. IL-6D and IL-6M show the same susceptibility to limited proteolytic attack, and exhibit identical far-UV CD-monitored urea-denaturation profiles with the midpoint of denaturation occurring at 6.0 +/- 0.1 M urea. However, IL-6D was found to dissociate prior to the complete unfolding of the protein, with a midpoint of dissociation of 3 M urea, suggesting that dissociation and dimerization occur when the protein is in a partially unfolded state. Based on these results, we suggest that IL-6D is a metastable domain-swapped dimer, comprising two monomeric units where identical helices from each protein chain are swapped through the loop regions at the "top" of the protein (i.e., the region of the protein most distal from the N- and C-termini). Such an arrangement would account for the antagonistic activity of IL-6D. In this model, receptor binding site I, which comprises residues in the A/B loop and the C-terminus of the protein, is free to bind the IL-6 receptor. However, site III, which includes Trp157 and residues in the C/D loop and N-terminal end of helix D, and perhaps site II, which comprises residues in the A and C helices, are no longer able to bind the signal transducing component of the IL-6 receptor complex, gp130.
...
PMID:Physicochemical characterization of an antagonistic human interleukin-6 dimer. 969 57

Stress mediators play a major role in inducing the hypermetabolic stress state in the liver after major injuries. The majority of studies on the effect of mediators on hepatocytes have focused on single factor effects or on the effect of very complex additives (e. g., serum), and there are no reports which have rigorously identified specific interactions between stress mediators. We used a factorial design experimental approach to evaluate the effects of a four to five day exposure to hormone (glucagon, hydrocortisone, and epinephrine) and cytokine [tumor necrosis factor-alpha (TNF-alpha) interleukin-1beta (IL-1beta) and interleukin-6 (IL-6)] stress mediators on stable cultures of rat hepatocytes. Both individual-factor effects and two factor interactions on the metabolism of urea, glucose, lactate, ketone bodies, albumin, and fibrinogen were evaluated. The cultured hepatocyte model exhibited physiologic responses to the applied stress mediators. While hydrocortisone and epinephrine had no effect, glucagon induced an increase in glucose and urea synthesis. Interleukin-6 increased fibrinogen and decreased albumin production. Furthermore, IL-6 and glucagon caused an increase in the ketone-body ratio (KBR = [acetoacetate]/[beta-hydroxybutyrate]), which is in equilibrium with the intramitochondrial NAD+/NADH. Tumor necrosis factor-alpha and IL-1beta, on the other hand, decreased the KBR. An important two-factor interaction between IL-1beta and IL-6 was identified, namely that IL-1beta effectively negates the positive effect of IL-6 on the KBR when both are present. These results provide further understanding of the effect of stress mediators on hepatic function and metabolism. These effects may have important implications in the pathogenesis of progressive organ dysfunction which often follows prolonged inflammatory states triggered by major injuries.
...
PMID:Metabolic effects of stress mediators on cultured hepatocytes. 1019 93

We evaluated the relationship between plasma fibrinogen concentration and the serum levels of interleukin-6 (IL-6), its soluble receptor, and their complex in patients with type 2 diabetes mellitus. The study comprised 57 patients with type 2 diabetes and 15 normal healthy controls. Serum levels of IL-6, soluble IL-6 receptor (IL-6R), and circulating IL-6/IL-6R complex were determined by enzyme-linked immunosorbent assays. Correlations between the different study parameters and serum IL-6, IL-6R, or IL-6/IL-6R complex levels were determined by multiple linear regression analysis. Any association between the different study parameters and the serum levels of IL-6, IL-6R, or IL-6/IL-6R complex were determined by stepwise linear regression analysis. The serum IL-6 level in diabetic subjects was significantly higher than in normal healthy controls (3.48 +/- 3.29 pg/ml vs 0.784 +/- 0.90 pg/ml, mean +/- SD, respectively, P = 0.0001). The specific optical density of the serum IL-6/IL-6R complex in diabetic patients was also significantly higher than in normal healthy controls, although there was no significant difference in the serum IL-6R level between diabetic patients and controls. The serum IL-6 concentration was correlated significantly with the HbA(1C) level (beta = 0.58, P = 0. 04) by multiple regression analysis. Stepwise regression analysis revealed that the levels of serum IL-6 (F = 8.251), HbA(1C) (F = 1. 08), and serum urea nitrogen (F = 5.603) were associated with the plasma fibrino gen concentration. These results suggest that hyperglycaemia and increased levels of serum IL-6 can increase the plasma fibrinogen concentration, one of the known risk factors for atherosclerosis in patients with type 2 diabetes mellitus.
...
PMID:Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. 1043 55

Growing (35 kg body weight) and finishing (85 kg body weight) swine challenged with endotoxin (Escherichia coli O55:B5) at a dose of either 2 or 20 microg/kg produced tumor necrosis factor (TNF)alpha in a dose-response relationship as measured by bioassay. Peak TNFalpha plasma levels were observed 1-2 hr post-challenge, returning to basal values 4 hr post-challenge. However, both an enzyme-linked immunosorbent assay specific for swine TNFalpha and total human TNFalpha demonstrated no dose-response relationship; peak plasma levels of immunoreactive TNFalpha were also observed 1-2 hr post-challenge. Maximal plasma interleukin-6 levels occurred 1-2 hr post-challenge and remained elevated through 8 hr post-challenge; there was no effect of lipopolysaccharide dose or metabolic status. Although the metabolic status of the animals also affected glucose levels, with growing animals exhibiting greater sensitivity compared with finishing animals, endotoxin-induced decreases in blood glucose levels were primarily dose-dependent. In contrast, changes in plasma urea nitrogen and free fatty acid (FFA) levels were strictly related to the metabolic status. Urea nitrogen levels were unchanged in growing swine, whereas they were increased in finishing swine and remained elevated 24 hr post-challenge. FFA levels in growing and finishing swine increased 3-6 hr post-challenge. FFA levels returned to basal values for finishing swine 24 hr post challenge, but in growing swine remained elevated 24 hr post-challenge. Plasma aspartate transaminase levels were increased through 24 hr post-challenge; animals given a dose of 20 microg/kg exhibited the greatest increase. Similarly, swine challenged with a dose of 20 microg/kg also exhibited the greatest increase in levels of conjugated bilirubin; there was no effect on unconjugated (free) bilirubin. These results demonstrate that endotoxin challenge of swine result in a pattern of changes that are dependent on both the dose of endotoxin used and the metabolic status of the animal examined.
...
PMID:Challenge differentially affects cytokine production and metabolic status of growing and finishing swine. 1062 26

A series of three aromatic to alanine mutants of recombinant murine interleukin-6 lacking the 22 N-terminal residues (DeltaN22mIL-6) were constructed to investigate the role of these residues in the structure and function of mIL-6. While Y78A and Y97A have activities similar to that of DeltaN22mIL-6, F173A lacks biological activity. F173A retains high levels of secondary structure, as determined by far-UV circular dichroism (CD), but has substantially reduced levels of tertiary structure, as determined by near-UV CD and (1)H NMR spectroscopy. F173A also binds the hydrophobic dye 1-anilino-8-naphthalenesulfonic acid (ANS) over a range of pH values and exhibits noncooperative equilibrium unfolding (as judged by the noncoincidence of monophasic unfolding transitions monitored by far-UV CD and lambda(max), with midpoints of unfolding at 2.6 +/- 0. 1 and 3.5 +/- 0.3 M urea, respectively, and the lack of an observable thermal unfolding transition). These are all properties of molten globule states, suggesting that the loss of activity of F173A results from the disruption of the fine structure of the protein, rather than from the loss of a side chain that is important for ligand-receptor interactions. Surprisingly, under some conditions, this loosened conformation is no more susceptible to proteolytic attack than the parent protein. By analogy with human IL-6, Phe173 in DeltaN22mIL-6 makes multiple interhelical interactions, the removal of which appear to be sufficient to induce a molten globule-like conformation.
...
PMID:The single mutation Phe173 --> Ala induces a molten globule-like state in murine interleukin-6. 1068 43

Skeletal muscle tissue from SIV-infected macaques was previously found to contain abnormally high sulfate and low glutathione levels indicative of an excessive cysteine catabolism. We now confirm the peripheral tissue as a site of massive cysteine catabolism in HIV infection and have determined the urinary loss of sulfur per time unit. The comparison of the sulfate concentrations of the arterial and venous blood from the lower extremities of 16 symptomatic HIV+ patients and 18 HIV- control subjects (study 1) revealed (1) that the peripheral tissue of HIV+ patients with or without highly active antiretroviral therapy (HAART) releases large amounts of sulfate and (2) that plasma sulfate, thioredoxin, and interleukin-6 levels are elevated in these patients. A complementary investigation of 64 asymptomatic HIV+ patients and 65 HIV- subjects (study 2) revealed increased plasma sulfate levels in the asymptomatic patients. The analysis of the daily urinary excretion of sulfate and urea of another group of 19 HIV+ patients and 22 healthy HIV- subjects (study 3) confirmed (1) that HIV+ patients experience a massive loss of sulfur and (2) that this loss is not ameliorated by HAART. The sulfur loss of asymptomatic patients was equivalent to a mean loss of about 10 g of cysteine per day. If extrapolated, this would correspond to an alarming negative balance of approximately 2 kg of cysteine per year under the assumption that the normal sulfate excretion equivalent to approximately 3 g of cysteine per day is balanced by a standard Western diet. The abnormally high sulfate/urea ratio suggests that this process drains largely the glutathione pool.
...
PMID:Massive loss of sulfur in HIV infection. 1071 Feb 8

The lack of backfiltration reduces plasma levels of C-reactive protein and interleukin-6. Paired filtration dialysis is the hemodialfitration technique that abolishes backfiltration. By physically separating convection from diffusion, it allows pure ultrafiltrate to be available during the entire session, so the ultrafiltrate can be regenerated and used as infusion fluid. On these premises, we have developed a European, open, randomised, multicentre study aimed at evaluating the effect of hemodiafiltration with on-line endogenous reinfusion (on-line HFR) on anemia. At least 130 chronically uremic hemodialysed (bicarbonate hemodialysis) stable patients with mild anemia (Hb between 9 and 11 g/dL) will be enrolled and normalized for iron stores by concomitantly repleting iron deposits (if ferritin <300 microg/L) and reducing the dose of erythropoietin to maintain Hb values within the range at enrollment (9-11 g/dL). Patients will be included in the study, randomized to the two treatments (test treatment: on-line HFR; control treatment: hemodiafiltration or modified forms) and followed up for nine months. Iron stores will be maintained within normal levels and the dose of erythropoietin will be kept constant. The primary question and response variable will be the mean monthly changes in hemoglobin levels over the period of nine months. As secondary questions and response variables, we will measure the nutritional status using a subjective global assessment, protein catabolic rate, urea generation rate and the dietician's assessment, serum concentrations of vitamins A, C, E and serum C-reactive protein.
...
PMID:The effect of hemodiafiltration with on-line endogenous reinfusion (on-line HFR) on anemia: design of a European, open, randomised, multicentre trial. European Collaborative Study. 1072 Feb 12

Metallothionein (MT) is a low-molecular-weight, sulfhydryl-rich, metal-binding protein that can protect against the toxicity of cadmium, mercury, and copper. However, the role of MT in arsenic (As)-induced toxicity is less certain. To better define the ability of MT to modify As toxicity, MT-I/II knockout (MT-null) mice and the corresponding wild-type mice (WT) were exposed to arsenite [As(III)] or arsenate [As(V)] either through the drinking water for 48 weeks, or through repeated sc injections (5 days/week) for 15 weeks. Chronic As exposure increased tissue MT concentrations (2-5-fold) in the WT but not in MT-null mice. Arsenic by both routes produced damage to the liver (fatty infiltration, inflammation, and focal necrosis) and kidney (tubular cell vacuolization, inflammatory cell infiltration, and interstitial fibrosis) in both MT-null and WT mice. However, in MT-null mice, the pathological lesions were more frequent and severe when compared to WT mice. This was confirmed biochemically, in that, at the higher oral doses of As, blood urea nitrogen (BUN) levels were increased more in MT-null mice (60%) than in WT mice (30%). Chronic As exposures produced 2-10 fold elevation of serum interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels, with greater increases seen by repeated injections than by oral exposure, and again, MT-null mice had higher serum cytokines than WT mice after As exposure. Repeated As injections also decreased hepatic glutathione (GSH) by 35%, but GSH-peroxidase and GSH-reductase were minimally affected. MT-null mice were more sensitive than WT mice to the effect of GSH depletion by As(V). Hepatic caspase-3 activity was increased (2-3-fold) in both WT and MT-null mice, indicative of apoptotic cell death. In summary, chronic inorganic As exposure produced injuries to multiple organs, and MT-null mice are generally more susceptible than WT mice to As-induced toxicity regardless of route of exposure, suggesting that MT could be a cellular factor in protecting against chronic As toxicity.
...
PMID:Metallothionein-I/II null mice are more sensitive than wild-type mice to the hepatotoxic and nephrotoxic effects of chronic oral or injected inorganic arsenicals. 1082 79

The chronopharmacokinetics and chronopharmacodynamics of cisplatin were studied in a mouse model to reveal the mechanisms of dosing time-dependent nephrotoxicity induced by daily administration. Chronotoxicity was tested by daily intraperitoneal injections of cisplatin (6mg kg(-1)) for 5 days at four time points (04:00, 10:00, 16:00 and 22:00h) in BALB/c mice (n = 6 in each group). After following the changes in body weight, serum concentrations of blood urea nitrogen (BUN) and creatinine obtained on day 6 were compared. The results showed diurnal variations in cisplatin toxicity, with the 04:00 and 16:00h time points the best and the worst, respectively. We then measured platinum concentrations in blood, liver and kidney and compared the results of the 04:00 and 16:00 h groups (n = 4 in each group). Kidney sensitivity to cisplatin alone, lipopolysaccharide (LPS) alone, cisplatin with LPS and saline (control) were also measured using a tissue culture system (a measurement system of interleukin-6 (IL-6) production) between the 04:00 and the 16:00 h groups (n = 4 in each group). These results showed no significant difference in platinum accumulation between the two groups. IL-6 production was higher in the 16:00 h group than in the 04:00 h group after saline injection alone (P < 0.05). Cisplatin treatment alone did not increase IL-6 production. However, IL-6 levels were markedly augmented by cisplatin with LPS. In conclusion, chrononephrotoxicity induced by daily cisplatin administration does not only depend on cisplatin accumulation, but might also depend on kidney sensitivity to diurnal variations in inflammatory reaction without direct cisplatin toxicity.
...
PMID:Time-dependent nephrotoxicity associated with daily administration of cisplatin in mice. 1119 78

In this study, we measured the mRNA levels of adrenomedullin (AM), C-type natriuretic peptide, vascular endothelial growth factor, interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) in peripheral blood mononuclear cells (PBMC) of 34 patients with lupus nephritis (LN) (15 active and 19 inactive) and 30 healthy volunteers. mRNA levels were measured using a real-time quantitative PCR METHOD: Compared with healthy volunteers, IL-6 mRNA levels were elevated in LN patients (P < 0.005), while AM mRNA levels were decreased (P < 0.05). Also, IL-6 mRNA levels were higher and AM mRNA levels lower in active LN patients compared with inactive LN patients. In addition, IL-6 mRNA levels positively correlated and AM mRNA levels negatively correlated with SLE disease activity index and laboratory findings, such as blood urea nitrogen, serum creatinine, 50% haemolytic unit of complement and urinary excretion of protein over 24 h. Furthermore, IL-6 mRNA levels were negatively correlated with AM mRNA levels within the same LN patients. With regard to pathological findings, our results showed that IL-6 mRNA levels were higher, and AM mRNA levels significantly lower in patients with a high activity index compared to those with a low activity index. Following treatment with prednisolone, IL-6 mRNA levels in active LN patients decreased and AM mRNA levels increased to levels comparable to those in inactive LN and healthy volunteers. In vitro studies further demonstrated that elevated IL-6 mRNA levels in active LN patient PBMC were suppressed by the addition of adrenomedullin. Our results suggest that an imbalance between IL-6 and AM levels may play an important role in the progression of SLE, and that the mRNA levels of these genes in PBMC may be used as a disease activity index for SLE.
...
PMID:Imbalance between interleukin-6 and adrenomedullin mRNA levels in peripheral blood mononuclear cells of patients with lupus nephritis. 1142 12

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>