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)

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotropic factor are a family of cytokines and neuronal differentiation factors which bind to composite plasma membrane receptors sharing the signal transducing subunit gp130. We have shown recently that IL-6 and leukemia inhibitory factor rapidly activate a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation, which then binds to IL-6 response elements of various IL-6 target genes. Here we demonstrate that APRF is activated by all cytokines acting through gp130 and is detected in a wide variety of cell types, indicating a central role of this transcription factor in gp130-mediated signaling. APRF activation is also observed in vitro upon addition of IL-6 to cell homogenates. Protein tyrosine kinase inhibitors block both the tyrosine phosphorylation and DNA binding of APRF. The factor was purified to homogeneity from rat liver and shown to consist of a single 87-kDa polypeptide, while two forms (89 and 87 kDa) are isolated from human hepatoma cells. As reported earlier, the binding sequence specificity of APRF is shared by gamma interferon (IFN-gamma) activation factor, which is formed by the Stat91 protein. Partial amino acid sequence obtained from purified rat APRF demonstrated that it is likely to be related to Stat91. In fact, an antiserum raised against the amino-terminal portion of Stat91 cross-reacted with APRF, suggesting the relatedness of APRF and Stat91. Altogether, these data indicate that APRF belongs to a growing family of Stat-related proteins and that IFN-gamma and IL-6 use similar signaling pathways to activate IFN-gamma activation factor and APRF, respectively.
Mol Cell Biol 1994 May
PMID:The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. 816 74

Recent evidence suggests that the alveolar macrophage-derived cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) play important roles in granulomatous diseases. Our objective was to quantify the mRNA for these cytokines in beryllium disease, a human granulomatous disease of known etiology. We hypothesized that alveolar macrophages and bronchoalveolar lavage fluid from patients with beryllium disease and sarcoidosis would express increased levels of mRNA and proteins, respectively, for TNF-alpha, IL-1 beta, and IL-6 compared with those of normal individuals. We performed bronchoalveolar lavage and used a quantitative polymerase chain reaction to determine alveolar macrophage-derived cytokine gene expression. We determined lavage fluid cytokine levels by enzyme-linked immunosorbent assay. In patients with beryllium disease (n = 23), we observed elevated macrophage mRNA expression for TNF-alpha and IL-6 when compared with that of normal subjects (n = 7). Sarcoidosis patients (n = 6) also had increased expression for TNF-alpha and IL-6 compared with that of normal volunteers. IL-1 beta expression was similar in all three groups. In patients with beryllium disease (n = 39), lavage fluid TNF-alpha concentration was higher than that of 16 normal subjects. Lavage fluid IL-1 beta and IL-6 levels did not differ among the groups. This is the first report of macrophage cytokine expression in beryllium disease. These novel findings suggest that macrophage expression of TNF-alpha and IL-6 may be important in the human granulomatous inflammatory response.
Am J Respir Cell Mol Biol 1994 May
PMID:Alveolar macrophages from patients with beryllium disease and sarcoidosis express increased levels of mRNA for tumor necrosis factor-alpha and interleukin-6 but not interleukin-1 beta. 817 12

Manifestations of HIV-1 infection such as fever, hypergammaglobulinemia, and interstitial pneumonitis may be due to increased production of inflammatory cytokines such as interleukin-1 and interleukin-6 (IL-6). Monocytes/macrophages of HIV-1-infected individuals have been noted to produce increased amounts of IL-6, as well as to have enhanced accessory cell function. These studies examined the ability of HIV-1 tat, an important HIV-1 regulatory gene, to modulate monocyte/macrophage function. In these experiments, HIV-1 tat-transfected THP-1 cells, a monocytic cell line, enhanced THP-1 immune accessory cell function in the presence of pokeweed mitogen and concanavalin A. HIV-1 tat-transfected cells also increased production of lipopolysaccharide-stimulated IL-6 mRNA and IL-6 protein. The ability of monocytes/macrophages to support HIV-1 production while exhibiting little or no cytopathic effects allows these cells to serve as a reservoir for the virus. The ability of HIV-1 tat to regulate cellular function in monocytes/macrophages may play an important part in the pathogenesis of HIV-1 infection.
Am J Respir Cell Mol Biol 1994 May
PMID:Modulation of accessory cell function and interleukin-6 production by the HIV-1 tat gene. 817 23

Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CYP1A2, CYP2C, CYP2E1, CYP3A, and epoxide hydrolase in primary human hepatocyte cultures. Steady state P-450 and epoxide hydrolase mRNA levels, as well as ethoxyresorufin-O-deethylase and nifedipine oxidation activities, which are mainly supported by CYP1A1/1A2 and CYP3A, respectively, were measured. Interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha were found to be the most potent depressors of P-450 enzymes. After 3 days of treatment, both mRNA levels and enzyme activities were depressed, typically by at least 40%, whatever the cytokine and the enzyme considered. Interferon-gamma also suppressed CYP1A2 and CYP2E1 mRNA levels and ethoxyresorufin-O-deethylase activity but had no effect on CYP3A and epoxide hydrolase mRNAs. In addition, interleukin-4 had the opposite effect, compared with other cytokines, on CYP2E1 mRNA, which was increased up to 5-fold; ethoxyresorufin-O-deethylase and nifedipine oxidation activities were not significantly affected. These results provide the first demonstration that various cytokines act directly on human hepatocytes to affect expression of major P-450 genes and that a wide range of responses can be observed among the enzymes for a given cytokine, suggesting that different regulatory mechanisms may be involved.
Mol Pharmacol 1993 Oct
PMID:Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. 823 20

Previous studies have revealed that human breast fibroblasts secrete the cytokine, interleukin-6 (IL-6) which stimulates the ability of MCF-7 human breast carcinoma cells to convert estrone (E1) to the biologically more active 17 beta-estradiol (E2). This is mediated by an increase in reductive 17 beta-hydroxysteroid dehydrogenase (17-HSD) activity. In the studies described here, we have extended our observations using the anti-estrogen, tamoxifen, to demonstrate that in a steady state, endogenous intracellular concentrations of E2 have no effects on reductive 17-HSD activity (E1-->E2), but are already maximally inhibitory for the oxidative reaction (E2-->E1). Increasing intracellular concentrations of E2, however, stimulated the reductive 17-HSD in a dose-dependent manner. IL-6 stimulated the reductive pathway and was synergistic with E2. IL-6 is most likely acting through an E2-dependent mechanism, since tamoxifen completely reversed the effects of E2 and IL-6 separately and in combination. These observations suggest that tamoxifen may reduce intratissular levels of E2 by directly increasing oxidative 17-HSD activity and by blocking the actions of paracrine factors such as IL-6 which increase reductive 17-HSD activity.
J Steroid Biochem Mol Biol 1993 Nov
PMID:The anti-estrogen tamoxifen blocks the stimulatory effects of interleukin-6 on 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. 824 Sep 83

Stable transfection of M1 myeloid leukemia cells with a temperature-sensitive mutant of p53 results in two phenomena that are manifested exclusively at the permissive temperature. On one hand, activation of wild-type p53 by the temperature shift induced an apoptotic type of cell death which could be inhibited by interleukin-6 (IL-6) (E. Yonish-Rouach, D. Resnitzky, J. Lotem, L. Sachs, A. Kimchi, and M. Oren, Nature 352:345-347, 1991). On the other hand, as reported in this work, activated p53 complemented the antiproliferative effects of IL-6 in M1 cells. A shift to the permissive temperature concomitant with or early after IL-6 treatment imposed a novel pattern of cell cycle arrest in which about 95% of the cells were retained within a G0-like quiescent state. This phase was characterized by 2N DNA content and low RNA and protein content. On the molecular level, activation of wild-type p53 transrepressed the c-myc gene but not the cyclin A, D1, or D2 gene, which are all independently suppressed by IL-6 in M1 cells. To further analyze whether c-myc inhibition mediates or complements p53 effects, the p53-transfected M1 cells were infected with a retroviral vector expressing deregulated c-myc, refractory to p53 or IL-6 action. It was found that the process of cell death was not interrupted at all in these M1 c-myc-p53 double transfectants, suggesting that the transrepression of c-myc is not a major obligatory event mediating p53-induced cell death. In addition, some of the antiproliferative effects of activated p53, manifested in the presence of IL-6, could still be transmitted in the background of constitutive c-myc. Yet the context of deregulated c-myc interfered with the final accumulation of cells within a G0-like phase, suggesting complementary interactions between the outcome of p53 activation and of c-myc suppression in the control of cell cycle arrest.
Mol Cell Biol 1993 Dec
PMID:Complementation by wild-type p53 of interleukin-6 effects on M1 cells: induction of cell cycle exit and cooperativity with c-myc suppression. 824 9

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.
Mol Cell Biol 1994 Jan
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

NF-IL6 and AP-1 family transcription factors are coordinately induced by interleukin-6 (IL-6) in a cell-type-specific manner, suggesting that they mediate IL-6 signals in the nucleus. We show that the basic leucine zipper (bZIP) region of NF-IL6 mediates a direct association with the bZIP regions of Fos and Jun in vitro. This interaction does not depend on the presence of their cognate recognition DNA elements or the posttranslational modification of either partner. NF-IL6 homodimers can bind to both NF-IL6 and AP-1 sites, whereas Fos and Jun cannot bind to most NF-IL6 sites. Cross-family association with Fos or with Jun alters the DNA binding specificity of NF-IL6 and reduced its binding to NF-IL6 sites. NF-IL6 isoforms that differ in the site of translation initiation have distinct transcriptional activities. Activation of a reporter gene linked to the NF-IL6 site by NF-IL6 is repressed by Fos and by Jun in transient transfection assays. Thus, association with AP-1 results in repression of transcription activation by NF-IL6. The repression is NF-IL6 site dependent and may have a role in determining the promoter and cell type specificity in IL-6 signaling.
Mol Cell Biol 1994 Jan
PMID:Fos and Jun repress transcription activation by NF-IL6 through association at the basic zipper region. 826 94

Fibroblasts of the pulmonary interstitium are intimately involved in the response of the lung to inflammation as well as in repair of injured tissues. The response of fibroblasts within an inflammatory site appears to be directed, in part, by peptide mediators. Neutral endopeptidase (NEP), a metallopeptidase on the surface membrane of fibroblasts, can inactivate various vasoactive peptides, including kinins and tachykinins. Because lung fibroblasts both secrete cytokines and respond to mediators within the immediate environment, NEP might be regulated by locally generated cytokines. We found that several cytokines, including interleukin-1 alpha (IL-1), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor, interleukin-6, and granulocyte macrophage colony-stimulating factor, enhanced activity of NEP on the surface of intact fibroblasts. In contrast, cultured pleural mesothelial cells had much lower levels of NEP than fibroblasts, and the enzyme was not enhanced by either IL-1 or TNF-alpha. Further studies with IL-1 showed that the effect required at least 6 h of exposure to the cytokine and depended upon final cytokine concentration. Combinations of IL-1 with other cytokines increased NEP activity beyond that in cells treated with individual cytokines, but combinations had less than additive effects. Selected pharmacologic agents indicated that the mechanism involves second messenger pathways. The cytokine effect on NEP was attenuated by indomethacin, an inhibitor of cyclooxygenase, by N-[2-(methylamino) ethyl]-5-isoquinolinesulfonamide dihydrochloride, an inhibitor of protein kinase, and by adenosine 3',5' cyclic monophosphothionate, an analog of cyclic adenosine monophosphate (cAMP) that competitively inhibits the cAMP signal pathway. It was mimicked by dibutyryl cAMP and by forskolin, an activator of adenyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Jan
PMID:Cytokines increase neutral endopeptidase activity in lung fibroblasts. 838 Feb 49

Interleukin-6 (IL-6) activation of the immediate-early gene junB has been shown to require both a tyrosine kinase and an unknown 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7)-sensitive pathway. Here we report the identification and characterization of an IL-6 immediate-early response element in the junB promoter (designated JRE-IL6) in HepG2 cells. The JRE-IL6 element, located at -149 to -124, contains two DNA motifs, an Ets-binding site (EBS) (CAGGAAGC) and a CRE-like site (TGACGCGA). Functional studies using variously mutated JRE-IL6 elements showed that both motifs were necessary and sufficient for IL-6 response of the promoter. The EBS of the JRE-IL6 element (JEBS) appears to bind a protein in the Ets family or a related protein which could also form a major complex with the EBSs of the murine sarcoma virus long terminal repeat or human T-cell leukemia virus type 1 long terminal repeat. The CRE-like site appears to weakly bind multiple CREB-ATF family proteins. Despite the similarity in the structure between the JRE-IL6 element and the polyomavirus enhancer PyPEA3, composed of an EBS and an AP1-binding site and known to be activated by a variety of oncogene signals, JRE-IL6 could not be activated by activated Ha-Ras, Raf-1, or 12-O-tetradecanoylphorbol-13-acetate. We show that IL-6 activates JRE-IL6 through an H7-sensitive pathway that does not involve protein kinase C, cyclic AMP-dependent kinase, Ca(2+)- or calmodulin-dependent kinases, Ras, Raf-1, or NF-IL6 (C/EBP beta). The combination of JEBS and the CRE-like site appears to form the basis for the selective and efficient response of JRE-IL6 to IL-6 signals, but not to signals generated by activated Ha-Ras, Raf-1, or protein kinase C.
Mol Cell Biol 1993 May
PMID:Identification of a novel interleukin-6 response element containing an Ets-binding site and a CRE-like site in the junB promoter. 838 18


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