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

Our present study was designed to clarify the mechanism by which the same megakaryocyte progenitor cells respond to various cytokines at different stages of megakaryocyte development. We examined the changes in mRNA expression of granulocyte macrophage colony-stimulating factor receptor beta-subunit (GM-CSFR beta-subunit), which was a common subunit of a high-affinity interleukin-3 receptor (IL-3R) and a high-affinity GM-CSFR, and interleukin-6 receptor (IL-6R) during megakaryocyte development in a human megakaryocytic leukemia cell line (CMK) which could proliferate and/or differentiate in the presence of 12-O-tetradecanoylphorbol 13-acetate (TPA), IL-3, GM-CSF, and IL-6. We found that GM-CSFR beta-subunit mRNA was expressed constitutively in CMK cells and was transiently down-regulated by TPA and IL-6, while the expression of IL-6R mRNA was increased by TPA in association with the differentiation of megakaryocytes. Furthermore, the TPA-induced down-regulation of GM-CSFR beta-subunit mRNA expression and its recovery were blocked by cycloheximide (CHX), a protein synthesis inhibitor, suggesting that these modulations required de novo protein synthesis. These findings imply that multi-lineage cytokines such as GM-CSF and IL-3 may contribute preferentially to the regulation of the earlier development of megakaryocyte progenitor cells with high densities of multi-lineage cytokine receptors, while IL-6 may be limited in its action to supporting the maturation of more differentiated megakaryocyte progenitor cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulation of GM-CSF receptor beta-subunit and interleukin-6 receptor mRNA expression in a human megakaryocytic leukemia cell line. 129 Sep 64

Growth of epithelial ovarian cancer is influenced by several factors including transforming growth factor-alpha and transforming growth factor-beta, macrophage colony stimulating factor, tumor necrosis factor-alpha, interleukin-1 and interleukin-6, c-erb B-2 (HER-2/neu), and mutant p53. Continued expression of the epidermal growth factor receptor, new expression of c-fms, and overexpression of HER-2/neu are associated with a poor prognosis. A number of cytokines have been used to treat patients with ovarian cancer, including interferon-alpha, interferon-gamma, tumor necrosis factor-alpha, and interleukin-2. Judging from preclinical models, interferon-gamma may be more active than interferon-alpha against human ovarian cancer. Although tumor necrosis factor-alpha can stimulate proliferation of some ovarian cancers, the cytotoxic activity of tumor necrosis factor-alpha has been amplified ex vivo by inhibitors of protein synthesis. Similar heterogeneity exists with regard to interleukin-1 where stimulation or inhibition of cell proliferation has been observed. Tumor-infiltrating lymphocytes from ascites fluid contain cells capable of major histocompatibility complex-restricted and major histocompatibility complex-nonrestricted cytotoxicity. Tumor-infiltrating lymphocytes and interleukin-2 have been combined with cytotoxic chemotherapy to treat advanced or recurrent disease. Bispecific monoclonal antibodies that react both with T cells and ovarian tumor cells have produced tumor inhibition in human tumor xenografts. Immunotoxins that contain OVB3 and pseudomonas exotoxin have been evaluated in a phase I clinical trial. Dose-limiting central neurotoxicity has been observed without tumor regression. A monoclonal antibody designated OVX1 has been developed against a high-molecular-weight mucinlike molecule associated with ovarian cancers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biology and therapy with biologic agents in gynecologic cancer. 145 11

Interleukin-6 (IL-6) is a multifunctional cytokine which acts on a wide variety of cells, exerting growth promotion, growth inhibition, or specific gene expression including cellular differentiation. The IL-6 receptor system consists of two membrane proteins, a ligand-binding chain (IL-6R) and a non-ligand-binding signal transducer, gp130, both of which belong to the cytokine receptor family. Binding of IL-6 to IL-6R triggers the association of IL-6R and gp130, and gp130 in turn transduces the signal. Despite its lack of IL-6 binding property, gp130 is involved in the formation of high-affinity IL-6 binding sites. This two-chain IL-6 receptor system can be applied to some other cytokine receptors, such as IL-3R, IL-5R and GM-CSFR which share a second signal-transducing component. A nuclear factor for controlling IL-6 gene expression (NF-IL6) is a leucine zipper-containing transcription factor and is homologous to C/EBP, a liver nuclear factor. NF-IL6 is also involved in the transcriptional regulation of various acute phase protein genes IL-6-triggered association of IL-6R and gp130 on hepatocytes, through intermediate steps including serine-phosphorylation of pre-existing NF-IL6 protein, leads to binding of NF-IL6 to IL-6-responsive elements and activation of acute-phase protein genes.
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PMID:IL-6 receptor and mechanism of signal transduction. 161 96

Two forms of the human granulocyte colony-stimulating factor (G-CSF) receptor (HuG-CSFR), differing only at the carboxyl terminus, were recently identified by cDNA cloning. In this report we show that transfection and subsequent expression of either cDNA clone in the interleukin-3 (IL-3)-dependent murine cell line BAF/BO3 converts the cells to G-CSF-responsiveness. The transfected cells bound HuG-CSF in a manner indistinguishable from the native receptors. Expression of a mutant form of the HuG-CSFR, with a deletion in the cytoplasmic domain, in BAF/BO3 cells failed to convert the cells to HuG-CSF-responsiveness. In a similar manner, expression of these two HuG-CSFRs in the interleukin-6 (IL-6)-dependent murine hybridoma B9 resulted in the ability of these cells to grow in HuG-CSF [corrected]. These results strongly suggest that sequences in the first 96 amino acids of the cytoplasmic domain of the HuG-CSFR are required for signal transduction in response to ligand binding.
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PMID:Alternative forms of the human G-CSF receptor function in growth signal transduction. 172 61

We quantified circulating and storage neutrophils, their precursors and progenitors, and mRNA for some of the cytokines involved in granulocytopoiesis, in newborn and adult mice following intrapulmonary inoculation of Escherichia coli. Four hours following inoculation of adult and newborn mice with a quantity of organisms 2 logs below the LD100, all animals were neutropenic. After 24 h, adults had recovered from the neutropenia but neonates had not (p < 0.001). Accelerated neutrophil production was evident in the infected adults, and correlated with the appearance of granulocyte colony-stimulating factor (G-CSF) transcripts in the liver, spleen, and lung, and interleukin-6 (IL-6) transcripts in the spleen and lung. An increase in neutrophil production was not observed in the neonates, and none of their organs tested had transcripts for either G-CSF or IL-6, but they did have transcripts for cytokines not involved in granulocytopoiesis; macrophage colony-stimulating factor and its receptor (c-fms). We speculate that the failure to increase neutrophil production in infected neonatal mice is the result of failure to increase production of relevant cytokines.
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PMID:The failure of newborn mice infected with Escherichia coli to accelerate neutrophil production correlates with their failure to increase transcripts for granulocyte colony-stimulating factor and interleukin-6. 750 13

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.
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PMID:Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. 752 88

We have previously shown that early human CD34high hematopoietic progenitors are maintained quiescent in part through autocrine transforming growth factor-beta 1 (TGF-beta 1). We also demonstrated that, in the presence of interleukin-3, interleukin-6, granulocyte colony-stimulating factor, and erythropoietin, TGF-beta 1 antisense oligonucleotides or anti-TGF-beta serum have an additive effect with KIT ligand (Steel factor [SF]), which suggests that they control different pathways of regulation in these conditions. This finding also suggests that autocrine TGF-beta 1 might suppress c-kit expression in primitive human hematopoietic progenitors. We have now distinguished two subpopulations of CD34high cells. One subpopulation expresses a c-kit mRNA that can be downmodulated by exogenous TGF-beta 1 within 6 hours. Another subpopulation of early CD34high cells expresses a low or undetectable level of c-kit mRNA, but its expression can be upmodulated within 6 hours by anti-TGF-beta. These effects disappear 48 hours after induction and cannot be maintained longer than 72 hours, even if TGF-beta 1 or anti-TGF-beta serum are added every day. Similar kinetics, although delayed, are observed with KIT protein expression. On the contrary, no specific effect of TGF-beta 1 was observed on c-fms, GAPDH, and transferrin receptor gene expression in these early progenitors. These results clarify the complex interaction between TGF-beta 1 and SF in normal early hematopoietic progenitors. SF does not switch off the TGF-beta 1 inhibitory pathway. Autocrine TGF-beta 1 appears to maintain these cells in a quiescent state, suppressing cell division by downmodulating the receptor of SF, a key cytokine costimulator of early progenitors.
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PMID:Early CD34high cells can be separated into KIThigh cells in which transforming growth factor-beta (TGF-beta) downmodulates c-kit and KITlow cells in which anti-TGF-beta upmodulates c-kit. 754 39

Hairy cell leukemia (HCL), a rare haematological disorder of B-cell origin, mainly presents with bone marrow infiltration, haematopoietic insufficiency, and splenomegaly. In some cases, osteolytic lesions can be observed. Many of these clinical features, especially haematopoietic insufficiency and osteolytic lesions are likely to be caused by soluble factors, such as cytokines. There is evidence that these factors are produced by the malignant hairy cells themselves, suggesting a paracrine pathway. The importance of autocrine as well as paracrine growth loops in growth regulation of HCL-cells is supported by a series of excellent studies, performed within the last few years. It could be clearly shown that cytokines are involved in this autocrine and paracrine regulatory process. The most important cytokines which should be mentioned in this respect are tumor necrosis factor alpha, (TNF alpha). Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-6 (IL-6) and B-cell-growth factor (BCGF). The role of other factors such as viruses and oncogenes remains rather unclear. Nevertheless, recent data suggest that the c-fms, which encodes for the macrophage colony stimulating factor (M-CSF) may be involved in the pathophysiological control of HCL growth. In this review, we summarise the important data and studies performed recently which shed light on the complex network of autocrine and paracrine growth regulation of HCL.
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PMID:Autocrine and paracrine regulation of neoplastic cell growth in hairy cell leukemia. 754 30

Using two different cell systems, we show that the cytoplasmic domain of the granulocyte-colony-stimulating factor receptor (G-CSFR) may be composed of at least two functional regions. The first, within the membrane-proximal 57 amino acids, is absolutely required to deliver a proliferative signal. This region contains two sequence motifs conserved between members of the hematopoietin receptor family. The second functional region resides between amino acids 57 and 96. This region is required for the induction of acute-phase plasma protein gene expression when the G-CSFR is transfected into human hepatoma cell lines. The G-CSFR-transfected hepatoma cells respond to G-CSF by increasing the production of the same set of plasma proteins as stimulated by interleukin-6, suggesting that the two cytokines share a common signal transduction pathway.
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PMID:Distinct regions of the human granulocyte-colony-stimulating factor receptor cytoplasmic domain are required for proliferation and gene induction. 768 Nov 46

The receptor for leukemia inhibitory factor (LIFR), in combination with the signal-transducing subunit for interleukin-6-type cytokine receptors, gp130, and LIF, activates transcription of acute-phase plasma protein genes in human and rat hepatoma cells and the vasoactive intestinal peptide gene in a human neuroblastoma cell line. To identify the regions within the cytoplasmic domain of LIFR that initiate signal transduction independently of gp130, we constructed a chimeric receptor by linking the extracellular domain of the granulocyte colony-stimulating factor receptor (G-CSFR) to the transmembrane and cytoplasmic domain of human LIFR. The function of the chimeric receptor protein in transcriptional activation was assessed by G-CSF-mediated stimulation of cotransfected cytokine-responsive reporter gene constructs in hepatoma and neuroblastoma cells. By using the full-length cytoplasmic domain and mutants with progressive carboxy-terminal deletions, internal deletions, or point mutations, we identified the first 150 amino acid residues of LIFR as the minimal region necessary for signaling. The signaling reaction appears to involve a cooperativity between the first 70-amino-acid region containing the two sequence motifs conserved among hematopoietin receptors (box 1 and box 2) and a critical sequence between residues 141 and 150 (box 3). Analogous analyses of the cytoplasmic domains of G-CSFR and gp130 indicated similar arrangements of functional domains in these receptor subunits and the requirement of a box 3-related motif for signaling.
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PMID:Multiple regions within the cytoplasmic domains of the leukemia inhibitory factor receptor and gp130 cooperate in signal transduction in hepatic and neuronal cells. 826 82


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