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)

Repeated subcutaneous injections of romurtide (N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine, MDP-Lys(L18), muroctasin; CAS 78113-36-7), a synthetic muramyl dipeptide derivative, increased significantly the number of peripheral neutrophils and monocytes in a dose-dependent fashion in healthy cynomolgus monkeys (Macaca fascicularis). The number of platelets was also increased significantly in monkeys with repeated dosing of romurtide. After single dosing of romurtide (1 mg/head), neutrophils counts showed a marked increase within 24 h and at 120 h after romurtide injection. Monocytes counts were decreased transiently until 8 h, but were increased persistently from 48 to 120 h after injection. Lymphocytes counts were stable throughout the experimental period except for a significant decrease until 24 h. In addition, romurtide stimulated blood neutrophils and monocytes in vivo for enhanced chemiluminescence (CL) responses to opsonized Escherichia coli. When peripheral monocytes from monkeys were incubated with various concentrations of romurtide in vitro, production of colony-stimulating factors (CSFs), interleukin-1 (IL-1) and interleukin-6 (IL-6) by the cells was enhanced significantly, indicating that the augmenting effects of romurtide on the production of various monokines including CSFs by monocytes are involved in the mechanisms of hematopoiesis and enhanced CL generation by phagocytic cells in vivo.
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PMID:Stimulatory effect of romurtide on hematopoiesis in monkeys. 204 13

N2-[(N-Acetylmuramoyl)-L-alanyl-D-isoglutaminyl-N6-stearoyl-L-lysine [MDP-Lys(L18), romurtide] is an immunopotentiating substance. In addition to neutrophilic leukocytosis, the effects previously found after the administration of this compound in both mice and humans were thrombocytosis and elevated levels of colony-stimulating factor (CSF) in peripheral blood. Although the exact mechanism of thrombopoiesis is not yet known, evidence has been accumulating that interleukin-6 (IL-6) plays an important role in the maturation of megakaryocytes, and the administration of IL-6 has been reported to induce a significant increase in blood platelets associated with promotion of megakaryocyte maturation. We measured the IL-6 levels in the culture supernatants of peripheral blood mononuclear cells (PBMCs), adherent cells and nonadherent cells in the presence of romurtide. Significant augmentation of IL-6 from PBMCs and adherent cells, but not nonadherent cells, was observed in the presence of romurtide in vitro.
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PMID:Production of interleukin-6 from macrophages by MDP-Lys (L 18), romurtide. 209 10

Using a functioning rat thyroid cell line (FRTL-5), we examined the effects of some cytokines, particularly interleukin-1 (IL-1) on the growth of thyroid cells. In 5H medium, namely Coon's modified Ham's F-12 medium supplemented with 5% calf serum and a five-hormone preparation consisting of insulin, hydrocortisone, transferrin, glycyl-L-histidyl-L-lysine acetate and somatostatin, IL-1 enhanced the growth of FRTL-5 cells detected by [3H]TdR incorporation. However, in 6H medium (5H medium plus bovine TSH), IL-1 inhibited the growth of FRTL-5 cells. Both effects were neutralized by the addition of anti-IL-1 antibody. Furthermore, IL-1 inhibited the growth of FRTL-5 cells induced by forskolin which is known as an adenylate cyclase activator. FRTL-5 cells have specific IL-1 receptors detected by the binding of 125I-labeled IL-1 alpha. By Scatchard plot analysis, the numbers and the dissociation constants of IL-1 receptors on FRTL-5 cells were shown to be 5225/cell and 8.69 x 10(-10) M. Interleukin-2, interleukin-6 and interferon-gamma (IFN-gamma) had no significant effects on the cell growth in 6H medium, while IFN-gamma and insulin-like growth factor I stimulated cell growth somewhat in 5H medium. These results suggest that IL-1 plays a regulatory role in the growth of thyroid cells through binding to the IL-1 receptors.
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PMID:Inhibitory effect of IL-1 on the TSH dependent growth of rat thyroid cells (FRTL-5). 212 71

Tissue transglutaminase belongs to a family of calcium-dependent enzymes, the transglutaminases that catalyze the covalent cross-linking of specific proteins by the formation of epsilon (gamma-glutamyl)lysine isopeptide bonds. The goal of this study has been the isolation and characterization of the human tissue transglutaminase gene promoter. Genomic DNA clones, spanning the 5' region of the gene, were isolated and the structure of the 5'-end of the human tissue transglutaminase gene was determined. 1.74 kilobases of flanking DNA were sequenced and were found to contain a TATA box element (TATAA), a CAAT box element (GGACAAT), a series of potential transcription factor-binding sites (AP1, SP1, interleukin-6 response element), and a glucocorticoid response elements. Transient transfection experiments showed that this DNA fragment included a functional promoter, which is constitutively active in multiple cell types.
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PMID:Isolation and characterization of the human tissue transglutaminase gene promoter. 773 Mar 52

The pleiotropic cytokine interleukin-6 (IL-6) has been predicted to be a protein with four antiparallel alpha-helices. On target cells, IL-6 interacts with a specific ligand binding receptor subunit (IL-6R), and this complex associates with the signal-transducing subunit gp130. Human IL-6 acts on human and murine cells, whereas murine IL-6 is only active on murine cells. The construction of chimeric human/murine IL-6 proteins has allowed us to define a region (residues 77-95, region 2c) within the human IL-6 protein that is important for IL-6R binding and a region (residues 50-55, region 2a2) that is important for IL-6R dependent gp130 interaction. Guided by sequence alignment and molecular modeling, we have constructed several IL-6 variants with point mutations in these regions and have tested them for receptor binding and signal initiation. Within region 2c, phenylalanine 78 was involved in receptor binding, whereas lysine 54 within region 2a2 participated in gp130 activation. Furthermore, some IL-6 variants with lysine 54 replacements could be used to construct muteins that retained receptor binding but failed to activate gp130. Such IL-6 muteins were efficient IL-6 receptor antagonists.
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PMID:Identification of single amino acid residues of human IL-6 involved in receptor binding and signal initiation. 887 26

Four novel 2,4-methano amino acids (MAAs, 1-aminocyclobutane-1-carboxylic acids) were synthesized. These include the basic MAA analogs of lysine (16), ornithine (5), and arginine (6) and the neutral methanovaline (22), related to proline. The above MAAs, as well as the MAA analog of homothreonine (7), were incorporated into the peptide chain of the immunomodulatory peptide tuftsin, Thr-Lys-Pro-Arg, known to enhance several biological activities mediated by phagocytic cells. The synthetic methano tuftsin analogs were assayed for their ability to stimulate interleukin-6 (IL-6) secretion by mouse peritoneal macrophages and for their stability in human serum toward enzymatic degradation. It was found that, at 2 x 10(-7) M, [MThr1]tuftsin (24) and an isomer of [MVal3]tuftsin (27a) were considerably more active than the parent peptide in augmentation of cytokine release. [MOrn2]Tuftsin (25) was equally potent. The analogs [MThr1]tuftsin (24) and [MOrn2]tuftsin (25), both pertaining to the proteolytically sensitive Thr-Lys bond of tuftsin, exhibited high resistance to enzymatic hydrolysis as compared to tuftsin. Using specific rabbit anti-tuftsin antibodies in a competitive enzyme-linked immunosorbent assay (ELISA) revealed that none of the MAA analogs can cross-react with tuftsin. It may indicate that the peptides assume global structures different than that of tuftsin.
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PMID:1-Aminocyclobutanecarboxylic acid derivatives as novel structural elements in bioactive peptides: application to tuftsin analogs. 894 97

The in vivo thrombopoietic activity of polyethylene glycol-modified interleukin-6 (MPEG-IL-6), in which 54% of the 14 lysine amino groups of IL-6 were coupled with PEG, was compared to that of native IL-6. Native IL-6 and MPEG-IL-6, which showed about 51% of the specific bioactivity of native IL-6, were administered subcutaneously to mice every 2 days for 7 days. Native IL-6 increased not only the peripheral platelet count, but also the plasma-IgG1 level in a dose-dependent manner. MPEG-IL-6 showed about 500 times higher thrombopoietic potency than native IL-6. Further, in comparison to native IL-6, MPEG-IL-6 did not enhance IgG1 production as much as it enhanced platelet production. MPEG-IL-6 significantly stimulated platelet recovery in mice treated with 5-fluorouracil, whereas the administration of native IL-6 had a negligible effect. The plasma half-life of MPEG-IL-6 was about 100-fold longer than that of native IL-6. The decrease in the plasma clearance of MPEG-IL-6 was thought to be due, in part, to the shielding of the proteolytic sites in the IL-6 molecule by the PEG chain. The uptake of IL-6 by the reticuloendothelial system, such as the liver and spleen, was markedly limited by PEGylation. The PEGylation of IL-6 markedly enhanced the blood-residency of IL-6, resulting in effective augmentation of its thrombopoietic activity and a marked decrease in its side-effects. These findings suggest that MPEG-IL-6 may be a potential candidate for thrombopoietic agent.
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PMID:PEGylation of interleukin-6 effectively increases its thrombopoietic potency. 903 69

Cytomedical therapy for human interleukin-6 transgenic mice (hIL-6 Tgm) was implemented by the intraperitoneal injection of alginate-poly(L)lysine-alginate (APA) membranes microencapsulating SK2 hybridoma cells (APA-SK2 cells) which secrete anti-hIL-6 monoclonal antibodies (SK2 mAb). IgG1 plasmacytosis in the hIL-6 Tgm was suppressed by a single injection of APA-SK2 cells, and the survival time of these mice was remarkably prolonged. The viable cell number and the SK2 mAb-secretion of APA-SK2 cells increased for at least one month both under culture conditions and in allogeneic recipients (in vivo). Moreover, SK2 mAb which were secreted from APA-SK2 cells injected into allogeneic recipients was detected in serum at high concentrations; 3-5 mg/ml from day 14 to day 50 post-injection. In contrast, the injection of free SK2 cells had no therapeutic effect on hIL-6 Tgm. These results strongly suggest that APA membranes microencapsulating cells which were modified to secrete molecules useful for the treatment of a disorder were effective as an in vivo long-term delivery system of bioactive molecules, as 'cytomedicine'.
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PMID:Cytomedical therapy for IgG1 plasmacytosis in human interleukin-6 transgenic mice using hybridoma cells microencapsulated in alginate-poly(L)lysine-alginate membrane. 906 Oct 40

Recent studies suggest that interleukin-1 beta (IL-1 beta) stimulates interleukin-6 (IL-6) production in human intestinal epithelial cells, but the intracellular mechanisms of this response are not known. In other reports, the nuclear factor-kappa B (NF-kappa B) regulated IL-6 production in certain cell types. We tested the hypothesis that IL-6 production in the enterocyte is associated with activation of NF-kappa B. Caco-2 cells, a human intestinal epithelial cell line, were grown in tissue culture whereafter they were treated with IL-1 beta (0.5 ng/ml). Cells were preincubated with pyrrolidine dithiocarbamate (PDTC; 10-500 microM), tosyl-lys-chloromethylketone (TLCK; 10-500 microM), or genistein (25-75 microM), all of which are known inhibitors of NF-kappa B. IL-6 levels in the culture media were measured after 24 hr by enzyme-linked immunosorbent assay (ELISA) and IL-6 messenger RNA (mRNA) levels were determined after 4 hr by competitive reverse-transcriptase polymerase chain reaction (RT-PCR). NF-kappa B activity was determined by electrophoretic gel mobility shift assay (EMSA). PDTC, TLCK, and genistein each inhibited IL-1 beta-induced IL-6 production by the Caco-2 cells in a dose-dependent fashion. These responses were also associated with a decrease in IL-6 mRNA levels. There was no NF-kappa B activity in untreated cells, but the addition of IL-1 beta resulted in the activation of NF-kappa B as determined by EMSA. The results suggest that IL-1 beta-induced IL-6 production in the enterocyte is associated with activation of NF-kappa B. The inhibition of IL-6 production by the NF-kappa B inhibitors indicates that the IL-6 production is regulated by NF-kappa B, although further experiments are needed to test that hypothesis.
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PMID:IL-6 production in human intestinal epithelial cells following stimulation with IL-1 beta is associated with activation of the transcription factor NF-kappa B. 920 60

This study assessed the impact of residual moisture, Tg, and excipient physical state of different formulations on the "in-process" and shelf-life stability of freeze-dried interleukin-6 (IL-6). The effect of an annealing procedure was also evaluated. Characterization of the lyophilizates was done by Karl Fischer titration, differential scanning calorimetry (DSC), and x-ray measurements. Analysis of protein stability was carried out by size exclusion chromatography (SEC), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and turbidity measurements. During freeze-drying, the most effective protection against aggregation was provided by completely amorphous formulations consisting of trehalose or sucrose either alone or in combination with glycine or mannitol. Other amorphous formulations like those of sucrose with lysine-HCl or dextran could not provide comparable stabilization. In lyophilizates containing a crystallized excipient such as glycine or mannitol, IL-6 suffered destabilization, which was less pronounced if an additional amorphous excipient was present. For the completely amorphous formulations, aggregation was prevented during a 9-month storage at 25 and 40 degrees C as long as the storage temperature did not exceed the Tg value of the lyophilizate, otherwise severe damage occurred. Formulations containing amorphous dextran or lysine-HCl could not effectively stabilize IL-6 even when stored below Tg. Annealing helped to improve cake robustness and appearance, but for lyophilizates containing an excipient crystallized by annealing an increase of IL-6 aggregation was observed despite a storage below Tg. Thus, the amorphous state of the excipients and a high Tg can be considered necessary conditions for preventing aggregation of freeze-dried IL-6. Whether the conditions are also sufficient depends on the choice of excipients. Destabilization can occur with some excipients despite their amorphous state as well as in the presence of crystallized excipients despite a storage below Tg. Compared to sucrose, trehalose is a more favorable excipient for protein lyophilization because it exhibits a higher Tg, possesses better stabilizing properties, and can reduce protein aggregation which may have been caused by annealing.
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PMID:Effects of formulation and process variables on the aggregation of freeze-dried interleukin-6 (IL-6) after lyophilization and on storage. 974 54


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