UNIPROT:P05231 - FACTA Search

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

The present studies have examined the effects of mitogens on induction of early response gene expression in normal peripheral blood T and Jurkat cells. Pokeweed mitogen (PWM) or anti-CD3 significantly increases c-jun messenger RNA (mRNA) levels in T cells. This transient PWM-related increase in c-jun transcripts is maximal after 15 to 30 minutes of exposure of T cells to PWM. PWM induces c-jun gene expression in a concentration-dependent manner. Moreover, PWM similarly induces expression of other genes coding for leucine zipper transcription factors, ie, jun-B and c-fos. Nuclear run on assays demonstrate that PWM treatment is associated with an increased rate of c-jun gene transcription. Transient expression assays with c-jun promoter fragments linked to the chloramphenicol acetyltransferase gene suggest that the PWM-induced increase in transcription is mediated by the AP-1 transcription factor complex. Moreover, treatment of T cells with actinomycin D to block further transcription before their culture with PWM suggests that the increase in c-jun gene expression by PWM is also regulated at least in part by a posttranscriptional mechanism. Cycloheximide does not alter c-jun mRNA induction by PWM. Finally, given that PWM induces B-cell differentiation in an interleukin-6 (IL-6)-mediated, T-cell-dependent manner, the relationship of c-jun and IL-6 gene expression in PWM-stimulated T cells was examined. The induction of IL-6 mRNA in T cells stimulated by PWM occurs after maximal induction of c-jun mRNA, at a time when the latter is no longer detectable. These findings suggest that PWM induces c-jun gene expression in T cells by a transcriptional and posttranscriptional mechanism and that AP-1 confers PWM inducibility of this gene. Because the IL-6 promoter has several potential transcriptional control elements, one of which is an AP-1-binding site, future experiments will evaluate the role of c-jun in the regulation of PWM-induced IL-6 synthesis by T cells.
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PMID:Regulation of c-jun gene expression in human T lymphocytes. 845 1

Adhesion of multiple myeloma (MM) cells to bone marrow stromal cells (BMSCs) not only localizes MM cells in the marrow microenvironment, but also triggers interleukin-6 (IL-6) secretion by BMSCs and related MM cell proliferation. In the present study, we characterized the regulation of IL-6 gene expression in BMSCs during MM cell adhesion. Adhesion of ARH-77, HS-Sultan, IM-9, and U266 MM cell lines to BMSCs and BMSC lines (LP 101 and AA 101) triggered 5-through 15-fold and 2-through 4-fold increases in IL-6 secretion, respectively. IL-6 mRNA transcripts were undetectable by Northern blotting in IM-9 MM cells or LP 101 BMSCs cultured alone; however, adherence of IM-9 cells to LP 101 cells induced a transient increase in IL-6 transcripts at 6 hours, followed by peak IL-6 secretion at 24 hours. To confirm increased IL-6 transcription and characterize its regulation, LP101 BMSCs were transiently transfected with full length and deletion fragments of the IL-6 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene. Transient transfection of LP101 BMSCs with plasmid containing an intact NF-kappa B site showed a 6.8 +/- 0.4-fold increase in CAT activity triggered by IM-9 MM cell adhesion (n = 3, P < .05). Transfection of LP 101 cells with plasmid containing a single base pair deletion from the NF-kapp B binding motif abolished the MM adhesion-induced increase in CAT activity, whereas transfection with plasmid containing three copies of synthetic NF-kappa B sequence resulted in an 8.1 +/- 0.7-fold increase in CAT activity related to MM adhesion (n = 3, P < .05). These data suggest that the NF-kappa B site is one of the essential regulatory elements for MM cell adhesion-induced IL-6 transcription in BMSCs. Electrophoretic mobility shift assays confirmed the involvement of NF-kappa B activation in regulating MM adhesion-induced IL-6 transcription in BMSCs. Further characterization of the upstream events in the signalling cascade regulating IL-6 may not only delineate mechanisms of IL-6 regulation during paracrine MM cell growth, but also provide new therapeutic strategies based on interruption of IL-6 mediated tumor cell growth.
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PMID:Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. 856 36

Several human heme oxygenase-1 promoter-driven chloramphenicol acetyltransferase constructs were examined in order to analyze promoter activity of the heme oxygenase-1 gene in microvessel endothelial cells. Heme oxygenase promoter activity was up-regulated by interleukin-6. This induction was shown to be down-regulated by glucocorticoids. Chloramphenicol acetyltransferase assays revealed that the promoter region (56 base pair) between -180 and -120 was responsible for up-regulation by growth factors, as well as for glucocorticoid-directed down-regulation. The same DNA fragments was shown to bind nuclear factor(s) from endothelial cells treated with dexamethasone. Formation of DNA protein complexes peaked after a 6-hour treatment. The DNA fragment was found to contain a sequence recognized by the STAT 3/acute phase response factor.
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PMID:Downregulation of the human heme oxygenase gene by glucocorticoids and identification of 56b regulatory elements. 857 87

Interleukin-6 (IL-6) is the major cytokine inducing transcription of human C-reactive protein (CRP) during the acute phase response. STAT (signal transducers and activators of transcription) family members, recently shown to be important mediators of the effects of many cytokines including IL-6, generally induce their effects by binding to palindromic sequences with TT(N)5AA motifs. We report an IL-6 responsive element in the proximal region of the human CRP 5'-flanking region that bears a TT(N)4AA motif, which we have termed CRP acute phase response element (CRP-APRE). In Hep3B cells, IL-6 but not interferon-gamma was capable of activating CAT constructs driven by the CRP promoter containing CRP-APRE. Overexpressed STAT3 was able to transactivate CRP-chloramphenicol acetyltransferase constructs through the CRP-APRE and was able to enhance endogenous CRP mRNA accumulation in response to IL-6. STAT3 (or an antigenically related molecule) bound to the CRP-APRE in response to IL-6. Overexpression of STAT3 in the presence of IL-6 was capable of inducing expression of a construct consisting of the CRP-APRE and a minimal thymidine kinase promoter lacking a C/EBP site. Taken together, these findings indicate that STAT3 participates in the transcriptional activation of CRP in response to IL-6.
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PMID:STAT3 participates in transcriptional activation of the C-reactive protein gene by interleukin-6. 862 22

Respiratory syncytial virus (RSV), the most common etiologic agent of epidemic pediatric respiratory disease, infects and replicates in the human airway epithelium, resulting in the induction of cellular gene products essential for immune and inflammatory responses. We describe the effect of RSV infection on nuclear factor-IL6 (NF-IL6) expression, a human basic domain-leucine zipper-containing transcription factor that alone in combination with other inducible transcription factors regulates the expression of cytokine and adhesion molecule genes. RSV-infected human type II pulmonary alveolar epithelial cells (A549) synthesize a single 45.7-kDa isoform of NF-IL6 rapidly and in a time-dependent manner. NF-IL6 is first detectable after 3 h of infection and continues to accumulate until 48 h (until the cells lose viability). NF-IL6 production could not be induced by UV-inactivated virus, demonstrating the requirement of viral replication for NF-IL6 synthesis. Immunoprecipitation after [35S]methionine metabolic labeling was done to investigate the mechanism for NF-IL6 production. There was robust NF-IL6 protein synthesis within RSV-infected (24 h) cells. Protein synthesis occurred without detectable changes in the abundance or size of the single 1.8-kb NF-IL6 mRNA. RNase protection assay of transfected chloramphenicol acetyltransferase reporter genes driven by either wild-type or mutated NF-IL6 binding sites show a virus-induced increase in NF-IL6-dependent transcription. These studies have demonstrated a novel inducible mechanism for translational control of NF-IL6 synthesis and identify this transcription factor as a potential effector of the host response to RSV infection.
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PMID:Inducible translational regulation of the NF-IL6 transcription factor by respiratory syncytial virus infection in pulmonary epithelial cells. 862 74

Serum amyloid A (SAA) is a plasma protein which has been associated with several diseases, including amyloidosis, arthritis, and atherosclerosis, and its abnormal expression, particularly in nonhepatic cells, is implicated in the pathogenesis of these diseases. Transfection and DNA-binding studies were performed to investigate the mechanism controlling cytokine-induced, nonhepatic expression of the SAA gene. We have identified a novel promoter, located between positions -280 and 224, that confers interleukin-6 (IL-6) inducibility to an SAA-chloramphenicol acetyltransferase reporter gene in both nonhepatic and hepatic cells. DNase I protection assays revealed, within this region, three homologous highly pyrimidine rich octanucleotide sequence motifs, termed SAA-activating sequences (SAS). Specific mutations within these three SAS motifs severely reduced IL-6-mediated induction of the reporter gene in transfected nonhepatic cells but not in liver cells. A nuclear factor activated by IL-6 in both hepatic and nonhepatic cells efficiently interacts with the SAS. The induction kinetics and cycloheximide sensitivity of this SAS-binding factor (SAF) suggested that de novo synthesis of this factor itself or an activator protein is essential. Loss of DNA-binding ability as a result of in vitro dephosphorylation, induction of SAA-chloramphenicol acetyltransferase reporter gene activity in the presence of genistein, a protein kinase inhibitor, further indicate that a phosphorylation step is necessary for the activation of SAF. Our results suggest that SAF is a key regulator of cytokine-mediated SAA gene expression in some nonhepatic cells.
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PMID:A novel cis-acting element is essential for cytokine-mediated transcriptional induction of the serum amyloid A gene in nonhepatic cells. 865 33

Endothelial cells (EC) play a key role in the inflammatory response, both by the production of proinflammatory cytokines and by their interaction with leukocytes. Molecular genetic analysis has demonstrated that functional NF-kappa B sites are involved in the transcription of interleukin-6 (IL-6), IL-8, and granulocyte-macrophage colony-stimulating factor (GM-CSF) genes in response to inflammatory mediators. Thus, we have explored the effect of two inhibitors of the NF-kappa B activation, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), on the production of these cytokines by EC. Both PDTC and NAC inhibited, in a dose-dependent manner, the synthesis of IL-6, IL-8, and GM-CSF induced by tumor necrosis factor (TNF)-alpha or bacterial lipopolysaccharides (LPS) in human umbilical vein endothelial cells (HUVEC). PDTC appeared to prevent IL-6, IL-8, and GM-CSF gene transcription, as it blocked the induction of specific mRNA by TNF-alpha or LPS. The TNF-alpha mediated transcriptional activation of a chloramphenicol acetyltransferase (CAT) plasmid containing three copies of the -72 kappa B binding site from the IL-6 promoter was abrogated by PDTC. According to transfection experiments, electrophoretic mobility shift assays (EMSA) demonstrated that the antioxidant prevented the induction of NF-kappa B DNA-binding activity by TNF-alpha. Under the same conditions, PDTC by itself or in combination with TNF-alpha, enhanced the DNA-binding activity of AP-1, as well as c-fos and c-jun mRNA levels. Altogether, these results indicate that the antioxidant PDTC specifically inhibits the transcription of IL-6, IL-8, and GM-CSF genes through the inhibition of the NF-kappa B activation, while increasing the expression of AP-1. Our data make evident the antiinflammatory and immunoregulatory potential of the pharmacological inhibition of the NF-kappa B activation. In addition, PDTC and related molecules may be a useful tool to explore the expression of genes involved in the inflammatory response.
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PMID:Pyrrolidine dithiocarbamate inhibits the production of interleukin-6, interleukin-8, and granulocyte-macrophage colony-stimulating factor by human endothelial cells in response to inflammatory mediators: modulation of NF-kappa B and AP-1 transcription factors activity. 889 14

The pancreatitis-associated protein I (PAP I) is a pancreatic secretory protein expressed in pancreas during acute pancreatitis but not in the healthy pancreas. The promoter of the PAP I gene thus represents a potential candidate to drive expression of therapeutic molecules to the diseased pancreas. In this work, we have constructed recombinant adenoviruses harboring the chloramphenicol acetyltransferase (CAT) gene driven by several fragments of the PAP I promoter and have characterized their properties in vitro and in vivo. In vitro studies showed that the transduction of the pancreatic cell line AR-42J with these adenoviruses led to low levels of CAT activity in basal conditions. After stimulation with a combination of interleukin-6 and dexamethasone or after induction of oxidative stress, CAT activity was strongly induced, a characteristic of the endogenous PAP I gene. Stimulation was maximal when constructs comprised 1253 base pairs of the PAP I promoter, upstream from initiation of transcription, and decreased with shorter fragments of 317, 180, 118 or 61 base pairs. The recombinant adenovirus containing the CAT gene under the control of the PAP I promoter fragment (-1253/+10) was also tested in vivo. Following administration by intravenous injection into mice, CAT activity was measured in several tissues 96 h later. In healthy animals, low but significant CAT activity was detected in pancreas, compared with near background values observed in the other tissues. When experimental acute pancreatitis was induced, CAT expression was strongly enhanced only in pancreas. In control experiments with adenoviruses in which the CAT gene was driven by the cytomegalovirus promoter, higher levels of expression were observed in all tissues. Expression was not modified after induction of acute pancreatitis. In conclusion, this study shows that (i) a recombinant adenovirus containing a fragment of the PAP I promoter allows specific targeting of a reporter gene to the mouse pancreas and (ii) expression of the reporter gene in pancreas is induced during acute pancreatitis. Adenovirus-mediated gene therapy of acute pancreatitis is therefore conceivable.
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PMID:The pancreatitis-associated protein I promoter allows targeting to the pancreas of a foreign gene, whose expression is up-regulated during pancreatic inflammation. 903 94

Retinoids inhibit the expression of migration inhibitory factor-related protein-8 (MRP-8), a marker of hyperproliferative or abnormal keratinocyte differentiation, in a retinoic acid receptor (RAR)-dependent manner in various cell culture systems. MRP-8 expression is also down-regulated in vivo in psoriatic lesions after topical application of an anti-psoriatic RARbeta/gamma-selective synthetic retinoid, tazarotene. We demonstrate that an MRP-8 promoter linked to a chloramphenicol acetyltransferase reporter (MRP8CAT) faithfully replicates the differentiation-specific regulation of the endogenous keratinocyte MRP-8 gene. Further, interferon gamma and serum-induced expression of MRP8CAT is inhibited by retinoid receptors in a ligand-dependent manner. We also show that NF-IL6 acts as a transcriptional enhancer of MRP-8, and that RARs inhibit MRP8CAT by inhibiting the enhancer action of nuclear factor-interleukin-6 (NF-IL6). The NF-IL6 antagonism function of RAR is a complex of the core of the DNA binding domain and the hydrophobic zipper region. This manuscript identifies NF-IL6 as another transcription factor, in addition to AP1, whose activity is inhibited by RAR in a ligand-dependent manner. The interdiction of NF-IL6-dependent signal transduction pathway by RARs may explain some of the therapeutic effects of retinoids in inflammatory and proliferative diseases.
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PMID:Retinoic acid receptor-nuclear factor-interleukin 6 antagonism. A novel mechanism of retinoid-dependent inhibition of a keratinocyte hyperproliferative differentiation marker. 932 72

Parathyroid hormone (PTH) functions in part by regulating osteoblast cytokine expression. We recently demonstrated that PTH induced a rapid and transient increase in interleukin-6 (IL-6) mRNA expression in rat bones in vivo. To determine the molecular basis of this effect, we analyzed the human IL-6 promoter fused (-1,179 to +9) with the chloramphenicol acetyltransferase (CAT) reporter gene in stable transfections into human osteoblast-like osteosarcoma SaOS-2 cells. We compared the effects of PTH on IL-6 expression with adenylate cyclase activator forskolin, PKC activator phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187, interleukin-1 alpha (IL-1 alpha), prostaglandin E-2 (PGE-2), RS-66271 (a parathyroid hormone-related peptide analog), and platelet-derived growth factor-BB (PDGF-BB). Analyses of cell clones showed that IL-6 promoter expression was extremely low in the unstimulated state. Exposure to PTH (0.001-100 nM) for 12 h stimulated CAT expression in a dose-dependent manner (200-500% of control). Treatment with IL-1 alpha was more potent than PTH in inducing transcription of the IL-6 promoter (900-1,000%). Activation of the cAMP-PKA pathway by treatment with forskolin induced a comparable level of induction with PTH. Together, the effects of PTH and forskolin were additive. RS-66271, previously shown to have PTH-like effects, induced a comparable level of IL-6 promoter expression. When examined together, PTH+RS-66271 effects were comparable to PTH effects alone. Exposure to PGE-2, PMA, PDGF-BB, or A23187 for 12 h did not significantly alter IL-6 promoter expression. These results demonstrate PTH, forskolin, the PTHrP analog RS-66271, and IL-1 alpha stimulate IL-6 expression by stimulating gene transcription. The response to forskolin suggests that the messenger system mediated by PKA is sufficient to induce IL-6 expression.
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PMID:Parathyroid hormone (1-34)-mediated interleukin-6 induction. 932 32

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