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

Interleukin-6 (IL-6) and gamma interferon (IFN-gamma) induce a partially overlapping set of genes, including the genes for interferon regulatory factor 1 (IRF-1), intercellular adhesion molecule 1 (ICAM-1), and the acute-phase protein alpha 2-macroglobulin. We report here that the rat alpha 2-macroglobulin promoter is activated by IFN-gamma in human hepatoma (HepG2) cells and that the IFN-gamma response element maps to the same site previously defined as the acute-phase response element (APRE), which binds the IL-6-activated transcription factor APRF (acute-phase response factor). As was reported for fibroblasts, the IFN-gamma-regulated transcription factor GAF is phosphorylated at tyrosine after IFN-gamma treatment of HepG2 cells. IFN-gamma posttranslationally activates a protein which specifically binds to the alpha 2-macroglobulin APRE. This protein is shown to be identical or closely related to GAF. Although APRF and GAF are shown to represent different proteins, their binding sequence specificities are very similar. APRF and GAF bind equally well to the APRE sequences of various acute-phase protein genes as well as to the IFN-gamma response elements of the IRF-1, ICAM-1, and other IFN-gamma-inducible genes. Transient transfection analysis revealed that the IFN-gamma response elements of the IRF-1 and ICAM-1 promoters are able to confer responsiveness to both IFN-gamma and IL-6 onto a heterologous promoter. Therefore, APRF and GAF are likely to be involved in the transcriptional induction of these immediate-early genes by IL-6 and IFN-gamma, respectively. Taken together, these results demonstrate that two functionally distinct hormones, IL-6 and IFN-gamma, act through common regulatory elements to which different transcription factors sharing almost the same sequence specificity bind.
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PMID:The signalling pathways of interleukin-6 and gamma interferon converge by the activation of different transcription factors which bind to common responsive DNA elements. 750 45

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

Interferons (IFNs), as well as some interleukins, growth factors, and hormones, all induce tyrosine phosphorylation of STAT1 and additional transcription factors of similar sizes. These factors are activated to translocate to nucleus and bind to enhancers of consensus sequence TTnCnnnAA (gamma-IFN activated sequence-like enhancers). In mammary cells or hybridoma B9 cells, four distinct tyrosine-phosphorylated transcription complexes activated by interleukin-6 (IL-6) and IFN-beta were observed: pIRFA and complexes I, II, and III (of increasing electrophoretic mobility). The factors have unequal affinities for enhancers of different genes; they are activated with distinct kinetics and to different extents by IL-6 and IFNs. The pIRFA band isolated from IL-6-stimulated B9 hybridoma cells revealed three DNA-interacting components: two large subunits of 91 and 98 kDa, as well as a small component of 46 kDa not seen in other complexes analyzed. One of the large pIRFA subunits may be APRF/STAT3, since pIRFA reacted with anti-APRF antibodies as do complexes I and II. However, pIRFA did not react with antibodies to STAT1, indicating STAT1 is not the other large component of pIRFA. Complex II, which reacted to anti-acute phase response factor antibodies also reacted to anti-STAT1 antibodies, whereas complex III reacted only to anti-STAT1 and was the only complex resistant to N-ethylmaleimide. By its multimeric subunit structure and its cytokine and enhancer sequence specificities, the slowly migrating pIRFA band appears as a novel tyrosine-phosphorylated transcription complex acting on a subset of gamma-IFN activated sequence-like enhancers.
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PMID:Interleukin-6 signaling via four transcription factors binding palindromic enhancers of different genes. 752 3

Supraphysiological levels of glucocorticoids, whether endogenous (Cushing's syndrome) or exogenous (glucocorticoid therapy), inhibit growth in children and immature animals. This effect has long been suspected to be due to glucocorticoid antagonism of GH action at the level of peripheral tissues. In the present study we demonstrate direct antagonism of GH action at the cellular level by the artificial glucocorticoid dexamethasone. Dexamethasone was found to inhibit the ability of GH to elicit several early events in GH signaling in 3T3-F442A fibroblasts. Dexamethasone (100 nM) for 24 h decreases by 50-75% GH-induced tyrosyl phosphorylation of mitogen-activated protein kinases ERK1 and ERK2, the transcription factor Stat3/APRF, the GH receptor-associated tyrosine kinase JAK2, and the GH receptor. These effects appear to be specific to GH. Dexamethasone does not inhibit induction of tyrosyl phosphorylation of ERK proteins by epidermal growth factor or phorbol myristate acetate, nor does it block induction of tyrosyl phosphorylation of Stat3/APRF by leukemia inhibitory factor or interleukin-6, or induction of JAK2 by leukemia inhibitory factor or interferon-gamma. Dexamethasone does not decrease the expression of ERK1 or -2, Stat3, or JAK2 proteins. Rather, the effects of dexamethasone on GH action appear to be due to a decrease in the number of GH receptors in the plasma membrane. Twenty-four-hour treatment with dexamethasone leads to a 50% decrease i GH binding, which Scatchard analysis suggests is due to a decrease in GH receptor number. These findings suggest that glucocorticoids antagonize cellular GH action by decreasing GH binding, suggesting a mechanism by which systemic glucocorticoids could antagonize GH action in peripheral tissues.
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PMID:Dexamethasone-induced antagonism of growth hormone (GH) action by down-regulation of GH binding in 3T3-F442A fibroblasts. 758 9

The product of the junB gene is a member of the AP-1 family of transcription factors that activate transcription by binding to TPA-responsive elements (TREs) within the promoters of target genes. Components of AP-1 are immediate-early genes whose expression is upregulated by a plethora of extracellular stimuli and are important in mediating cellular proliferation and differentiation. Such stimuli include the pleiotropic cytokine interleukin-6 (IL-6) which plays a role in immune and inflammatory responses and ciliary neurotrophic factor (CNTF) which enhances survival and differentiation of neurons and glia. We have analysed expression from junB promoter-CAT reporter constructs in HepG2 cells and found that a region between -196 and -91 can mediate response to IL-6 and CNTF and was able to confer responsiveness to a heterologous promoter. We further show by gel retardation analysis that distinct nuclear factors induced by IL-6 specifically bind to this interleukin-6 response element (IRE). This region contains both a putative ETS- and a STAT-transcription factor binding site. We show by mutational analysis and supershift data that the IL-6 induced complex indeed contains the transcription factor APRF/Stat3 that is both necessary and sufficient for activation. Interestingly this site does not appear to bind Stat1 itself, as shown by supershift analysis and a lack of response to IFN-gamma both at the DNA-binding and transcriptional level. Furthermore, we demonstrate that the junB IRE-binding activity induced by IL-6 requires tyrosine kinase activity, whereas induced transactivation of IRE-constructs additionally occurs through an H7-sensitive pathway that is p21ras-independent, implicating serine/threonine kinases in the transactivation of IRE-binding factors.
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PMID:Transcriptional regulation of the junB promoter: analysis of STAT-mediated signal transduction. 789 39

alpha 2-Macroglobulin (alpha 2M) is expressed at high levels in the corpus luteum of pregnant rats in response to PRL and rat placental lactogens. These studies document that PRL induction of alpha 2M mRNA occurs rapidly in granulosa cells differentiated to the preovulatory phenotype in the presence of FSH and steroid, is hormone specific [induced by PRL but not by LH or interleukin-6 (IL-6)], and involves tyrosine kinase activity. To analyze the cellular signaling events stimulated by PRL, transient transfections of granulosa cells and electrophoretic mobility shift assays were done using the IL-6 response element (IL-6RE) of the alpha 2M promoter. The IL-6RE consists of two gamma-activating like sequences (GAS) that bind the acute phase response factor (APRF/Stat 3) in rat liver and the mammary gland factor (MGF/Stat 5) from mammary tissue. By transfecting various alpha 2M promoter-luciferase reporter transgenes into the granulosa cell cultures, we show that the GAS-like sites together with the minimal -48 base pairs of the alpha 2M promoter can confer PRL inducibility to the luciferase reporter gene. These same GAS-like sequences of the alpha 2M promoter were used to analyze the DNA-binding activity of proteins in whole cell extracts prepared from differentiated granulosa cells exposed to PRL for 0.25, 0.5, 4, and 20 h. PRL rapidly stimulated the binding of a specific protein to labeled alpha 2M GAS-like oligonucleotide, and this PRL-induced binding activity was shown to contain Stat 5 but not Stat 1 or Stat 3, using specific antibodies in the electrophoretic mobility shift assays. Because both Stat 5 and Stat 3 proteins are present in the whole cell extracts of differentiated granulosa cells, PRL appears to activate detectable amounts of Stat 5 (and not Stat 3). Thus, the initial induction of the alpha 2M gene by PRL in differentiated rat granulosa cells involves, at least in part, the activation (tyrosine phosphorylation?) of Stat 5.
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PMID:Prolactin induction of the alpha 2-Macroglobulin gene in rat ovarian granulosa cells: stat 5 activation and binding to the interleukin-6 response element. 882 57

The mouse Bp3 antigen is a variably glycosylated phosphatidylinositol-linked cell surface glycoprotein expressed on early B and T lineage cells, myeloid cells, intestinal epithelial cells, and a discrete population of reticular cells in peripheral lymphoid tissues. The deduced amino acid sequence of Bp3 cDNA shares significant similarity to human and mouse CD38 and molluscan ADP-ribosyl cyclase, enzymes that generate the calcium mobilizing agent cyclic ADP-ribose from NAD. In this study, we cloned and characterized the Bp3 gene. The gene consists of nine exons and spans approximately 27 kilobases. The overall exon organization is very similar to that reported for the ADP-ribosyl cyclase gene in the mollusc Aplysia kurodai. The Bp3 gene is located on mouse chromosome 5 very near the gene for CD38, suggesting that this family arose by gene duplication. The major transcriptional start site of the Bp3 gene in a pro-B cell line (-17 from the ATG start codon) contains a weak initiator sequence. The upstream region lacks a TATA box, but contains consensus recognition sequences for the PU. 1, Ikaros/LyF-1, E2A, and TCF-1 transcriptional factors that regulate gene expression in lymphoid and myeloid cells. Consensus motifs for cytokine responsive factors NF-IL6/C-EBP, H-APF-1/APRF, and AP-1 are also present in the flanking region, and interleukin-6 treatment enhances expression of the Bp3 antigen by a myeloblastoid cell line.
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PMID:Genomic organization and chromosomal localization of the mouse Bp3 gene, a member of the CD38/ADP-ribosyl cyclase family. 888 Oct 35

The CCAAT/enhancer-binding protein delta (C/EBP delta) transcription factor is known to be rarely expressed but sharply induced at an early stage of the acute phase response. To investigate the regulation mechanisms for this induction, the 5'-flanking region of the rat C/EBP delta gene was isolated. Functional analyses involving transfection and footprinting indicated that the upstream region up to - 175 bp is sufficient for the full basal activity in rat fibroblast 3Y1 cells. At least three cis-elements including a GC box are involved in this activity. When HepG2 cells were treated with interleukin-6 (IL-6), C/EBP delta mRNA was rapidly induced. Transfection and gel shift analyses identified the binding site for the acute phase response factor/signal transducers and activators of transcription (APRF/STAT3). These findings strongly indicate that C/EBP delta gene expression is mediated by APRF/STAT3, which is phosphorylated for the activation through the IL-6 receptor when cells are treated with IL-6, and trans-activates the other acute phase response genes.
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PMID:CCAAT/enhancer-binding protein delta gene expression is mediated by APRF/STAT3. 916 25