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)

Recombinant human interleukin-6 (IL-6), expressed in Chinese hamster ovary cells, has heterogeneous N-termini of Ala1 and Val3, as does naturally occurring IL-6. This heterogeneity is thought to be caused by difficulty in cleavage of the signal sequence. To obtain homogeneous IL-6, Pro at -1 was exchanged for Ala by site-directed mutagenesis. Alternatively, the signal sequence was replaced with that of human granulocyte-colony-stimulating factor. In both cases, the IL-6 designed to start with Ala1 was still heterogeneous, while the IL-6 designed to start with Val3 showed a homogeneous N-terminus. It is suggested that the heterogeneity of the N-terminus is caused not only by the signal sequence, but also by the succeeding sequences of the mature protein. Only a portion of recombinant human IL-6 is N-glycosylated. Asn46, being exchanged for Gln by site-directed mutagenesis, was confirmed to be partially N-glycosylated. The defective N-glycosylation was assumed to be caused by interference or tension from a disulfide bond near the N-glycosylation site. To verify this hypothesis, the Cys45 and Cys51 forming the disulfide bond were exchanged for Ser. The N-glycosylated species became predominant upon this substitution, suggesting that formation of the disulfide bond is a cause of the defective N-glycosylation.
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PMID:Improvement in the heterogeneous N-termini and the defective N-glycosylation of human interleukin-6 by genetic engineering. 144 88

The aim of this study was to establish a cytokine-free, serum-free system which would enable the long-term survival and proliferation of human peripheral blood monocytes. Monocytes were isolated from peripheral blood mononuclear cells (PBMC) by adherence to untreated plastic petri dishes and maintained up to 6 weeks in serum-free medium (SFM) consisting of IMEM, insulin, transferrin, sodium selenite and BSA. Maximal cell proliferation occurred during the first 2 weeks of culture and corresponded to the appearance of large numbers of pure, nonadherent culture-derived macrophages. Monocyte maturation was characterised by the modulation of specific cell surface antigens. The percentage of cells staining for the transferrin receptor increased with time, whereas the percentages of cells expressing CD11b, CD11c and HLA-DR remained greater than 60% for the 15 days studied. The mean fluorescent intensities (MFI) of all these antibodies increased significantly with time. The only differences found between the adherent and nonadherent cells, using the above antibodies, were with the MFI for CD11b and CD11c. In both cases, the intensity of staining was significantly greater in the adherent cells. Estimation of cytokine production by cells maintained for 5 weeks in SFM found that they constitutively produced large amounts of macrophage colony-stimulating factor (M-CSF) in the absence of any exogenous stimuli. These cells were also found to secrete high levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) during the 1st week and granulocyte macrophage colony-stimulating factor (GM-CSF) during the 3rd week. However, the addition of exogenous GM-CSF (5 U/ml, S5) was found to significantly inhibit monocyte proliferation up to 17 days. This is the first report of proliferation associated with long-term survival of culture derived macrophages in a serum-free, cytokine-free system.
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PMID:Monocyte proliferation in a cytokine-free, serum-free system. 151 90

The human erythroleukemia (K562) cell line is induced to differentiate into megakaryocytic cells by treatment with the tumor promoter phorbol myristate acetate (PMA). PMA-induced differentiation is characterized by (1) almost complete cessation of cellular proliferation, (2) expression of the megakaryocytic cell surface marker glycoprotein IIb/IIIa (gpIIIa), (3) increased secretion of granulocyte/macrophage-colony stimulating factor (GM-CSF) and (4) increased secretion of interleukin-6 (IL-6). PMA-induced differentiation is dose-dependent with maximal activity seen at 10 nM PMA. In contrast, bryostatin (bryo), a structurally distinct protein kinase C (PKC) activator, fails to induce megakaryocytic differentiation or growth arrest at the concentrations tested (0.01-100 nM). Rather, bryo inhibits PMA-induced growth arrest and megakaryocytic differentiation in a dose-dependent fashion (full inhibition at 100 nM). The divergent biological effects of PMA and bryo correspond to the differential activation and translocation of PKC isotypes in K562 cells. PKC isotype analysis demonstrates that undifferentiated cells express both alpha and beta II PKC but no detectable beta I, gamma or epsilon PKC. Treatment of cells with either PMA or bryo leads to rapid translocation of both alpha and beta II PKC from the cytosol to the non-nuclear particulate fraction. However, bryo also induces selective translocation of beta II PKC to the nuclear membrane.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Protein kinase C isotypes in human erythroleukemia cell proliferation and differentiation. 152 49

We have constructed several hybrid human interleukin-6 (IL-6) variants in which the carboxyl-terminus, which includes a receptor binding site of IL-6 has been replaced with the C-terminus of various proteins homologous to human IL-6. IL-6 hybrids with the C-terminus of human growth hormone and human granulocyte-colony stimulating factor maintain part of the biological activity of human IL-6. Replacing the C-terminus of human IL-6 with the C-terminus of mouse and rat IL-6 resulted in a normal or increased activity on a mouse cell line; however, this gave a low (to 200-fold less) activity on a human cell line compared to wild-type human IL-6. We therefore conclude that the C-terminus of IL-6 plays an important role in the species specificity of IL-6.
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PMID:Construction and functional analysis of hybrid interleukin-6 variants. Characterization of the role of the C-terminus for species specificity. 163 83

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli-derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.
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PMID:Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha. 169 93

Marrow stromal cells are thought to regulate hematopoiesis by producing colony-stimulating factors (CSFs) and other cytokines, either constitutively or in response to mediators such as interleukin-1 alpha (IL-1 alpha) or tumor necrosis factor-alpha (TNF alpha). The mechanisms by which these inflammatory cytokines induce CSF expression in stromal cells are not fully defined. In this study, we used human marrow stromal cells transformed by simian virus 40 (SV-MSCs) to study growth factor and cytokine gene regulation in response to IL-1 alpha and TNF alpha. IL-1 alpha induced significant and prolonged increases in steady-state mRNA levels for interleukin-6 (IL-6), interleukin-1 beta (IL-1 beta), granulocyte-macrophage CSF (GM-CSF), and, to a lesser extent, granulocyte-CSF (G-CSF); this induction was not dependent on new protein synthesis. Nuclear run-on analyses showed that IL-1 alpha transcriptionally activated the genes for IL-6, GM-CSF, and IL-1 beta, while TNF alpha transcriptionally induced expression of IL-6 and IL-1 beta. Furthermore, mRNA for IL-6 and IL-1 beta was dramatically superinduced by the combination of cycloheximide and TNF alpha. When SV-MSCs were cultured in semisolid medium, they formed colonies of blast-like cells that, when replated on plastic, resumed adherent growth. These "colony-derived" cell lines, unlike the parental SV-MSCs from which they were derived, constitutively expressed colony-stimulating activity and mRNA for GM-CSF, G-CSF, IL-6, and IL-1 beta. In this report, we show that the expression of IL-6 and IL-1 beta mRNA in the colony-derived cell lines was due, at least in part, to constitutive transcriptional activation of these genes (similar to the findings in IL-1 alpha- and/or TNF alpha-stimulated parental SV-MSCs). However, in contrast to the transcriptional activation of the GM-CSF gene seen in cytokine-induced parental SV-MSCs, GM-CSF transcripts accumulated in the colony-derived cell lines by a posttranscriptional mechanism.
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PMID:Regulation of cytokine and growth factor gene expression in human bone marrow stromal cells transformed with simian virus 40. 169 28

We examined the ability of conditioned medium (CM) generated by human upper airway epithelial (Ep) cells from normal (NN) and inflamed, allergic rhinitis (AR) and nasal polyp (NP) tissues to induce monocytic differentiation of hemopoietic progenitors of the HL-60 myeloid leukemia cell line in vitro. In HL-60 cells cultured in RPMI with 10% FBS, there was differentiation to 0.4 +/- 0.4% monocytic cells. NN-, AR-, and NP-EpCM induced differentiation to 23 +/- 6%, 42 +/- 11%, and 71 +/- 10% monocytic cells, respectively. EpCM also induced isolated peripheral blood nonadherent mononuclear cells to express monocyte/macrophage-specific antigens as detected by immunohistochemistry using FMC-32 monoclonal antibodies (anti-CD14). We also examined the cytokine content of these EpCMs and found that they contained granulocyte/macrophage colony-stimulating factor (GM-CSF): 126 +/- 35, 198 +/- 22, and 489 +/- 118 pg/ml for NN-, AR-, and NP-EpCM, respectively. These CMs also contained granulocyte-CSF (G-CSF) and interleukin-6 (IL-6), but there were no significant differences between normal and inflamed tissue-derived cell supernatants. No macrophage-CSF (M-CSF) was detected in these EpCMs. Recombinant human GM-CSF, G-CSF, and IL-6, alone and in combinations, at doses similar to or greater than those found in the EpCMs, did not induce comparable monocytic differentiation of HL-60 cells. Preincubation of the EpCM with neutralizing anti-GM-CSF, anti-G-CSF, or anti-IL-6 antibodies did not significantly inhibit the monocytic differentiation induced by the EpCM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monocyte-macrophage differentiation induced by human upper airway epithelial cells. 170 10

The regulation of granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6) mRNA was studied in human adherent monocytes in response to the protein kinase C activator, oleolyl-acetylglycerol (OAG), the calcium-ionophore A23187 and the cyclic AMP elevating agents, dibutyryl c-AMP (DBcAMP), cholera toxin and isobutyl-methylxanthine (IBMX). G-CSF and IL-6 transcripts were simultaneously expressed in response to OAG, A23187, DBcAMP, IBMX and cholera toxin. However, the time course demonstrated a difference; a rapid induction by OAG and A23187 and a delayed pattern by cAMP elevating agents. In addition it appeared that the induction of CSFs by DBcAMP was independent of the adherence procedure or the presence of fetal bovine serum but could be counteracted by the simultaneous addition of H8, an inhibitor of the cAMP dependent kinases. Finally, experiments were performed to study in how far comparable mechanisms operate in other cell types. Human fetal lung fibroblasts were stimulated with A23187, DBcAMP and OAG. All these agents induced simultaneous expression of G-CSF and IL-6 mRNA and secretion of proteins, indicating that different signalling pathways exist in both cell types which regulate the expression of both genes.
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PMID:Simultaneous expression and regulation of G-CSF and IL-6 mRNA in adherent human monocytes and fibroblasts. 171 Apr 80

This study sought to determine whether endogenous tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and granulocyte-colony-stimulating factor (G-CSF) were detectable in sera of lipopolysaccharide (LPS)-treated cancer patients. Twenty patients received an intravenous bolus of purified LPS from Salmonella abortus-equi (4.0 ng/kg). Patients were pretreated with ibuprofen (1,600 mg) to prevent constitutional side effects like fever and chills. Serum TNF-alpha levels increased from less than 0.01 ng/ml before treatment up to maximal levels of 21 ng/ml, peaking 1.5 h after LPS injection. Similarly, serum IL-6 concentrations increased from less than 0.01 to 11 ng/ml, but peak levels were obtained 30 min later than TNF-alpha. Circulating G-CSF appeared still later than TNF-alpha and IL-6. It was detectable within 3 h and peaked 6 h after LPS injection. Parallel to the release of the above cytokines a marked increase in granulocyte counts was observed. In all patients administration of LPS led to an acute-phase response as measured by C-reactive protein.
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PMID:Treatment of cancer patients with endotoxin induces release of endogenous cytokines. 171 15

Colony-stimulating factors are a family of glycoproteins instrumental in regulation of hematopoiesis and inflammation. Clinical effects of various colony-stimulating factors have been reported in murine and human hosts. This review summarizes findings from some clinical trial evaluations of macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, interleukin-1, interleukin-3, interleukin-4, interleukin-5, interleukin-6, and interleukin-7 administration to other species. These factors stimulate clonal expansion of progenitor cells in the bone marrow, induce differentiation of various cell lineages to a mature phenotype, and, in some cases, enhance the effector activities of immune cells. Each colony-stimulating factor has distinct lineages of bone marrow cells upon which they act, although there is some overlap in lineage activity and synergy between colony-stimulating factors. The close relationship in biological activity among different colony-stimulating factors is also reflected at the genomic level at which genes for some hematopoietic growth factors have been mapped to a region of human chromosome 5. Recently, colony-stimulating factor administration to cattle and its potential application to disease control in bovine preventive medicine programs has been investigated. Data from recent hematological, immunological, and intramammary bacterial (Staphylococcus aureus and Klebsiella pneumoniae) challenge studies in dairy cows are reviewed. These studies, with limited numbers of cows, found that rate of new infections, as well as duration and severity of infection, were reduced by pretreatment of cows with granulocyte-colony stimulating factor. The dose-dependent hematological and immunomodulatory effects of granulocyte colony-stimulating factor administration may explain reduced severity and incidence of mastitis in dairy cows given granulocyte colony-stimulating factor.
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PMID:Immunobiology of hematopoietic colony-stimulating factors: potential application to disease prevention in the bovine. 172 1


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