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

Recent studies have indicated that the leukemia inhibitory factor (LIF) induces secretion of interleukin-6 (IL-6) in myeloid cells. We here show that synthesis of IL-6 by human mononuclear phagocytes exposed to recombinant human (rh) LIF is preceded by an increase of IL-6 transcript levels as a result of transcriptional activation of the IL-6 gene. Analysis of deleted fragments of the IL-6 promoter indicated that transcriptional activation of the IL-6 promoter was associated with enhanced binding activity of the transcription factor nuclear factor (NF)-kappa B. Binding of activation protein (AP)-1 and NF-IL-6, also known to transcriptionally activate the IL-6 promoter, was not inducible by LIF. Furthermore, introduction of the NF-kappa B sequence into a heterologous promoter construct, but not of AP-1- and NF-IL-6-binding sequences, conferred inducibility by LIF to this promoter. Deletion of the NF-kappa B binding site in the IL-6 promoter was associated with loss of inducibility by LIF, lending further support for the notion that the NF-kappa B binding site is crucial for LIF-mediated induction of the IL-6 promoter. Taken together, our results show that rhLIF induces IL-6 gene expression in mononuclear phagocytes through transcriptional gene activation involving NF-kappa B.
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PMID:Involvement of nuclear factor-kappa B in induction of the interleukin-6 gene by leukemia inhibitory factor. 1101 49

We report the cloning and sequencing of a 1252 base pairs (bp) DNA fragment containing the bovine interleukin-6 (IL-6) gene promoter. This fragment was isolated from a bovine genomic library constructed in the lambda GEM11 vector. Comparison with human, murine and rat IL-6 gene promoters reveals a high degree of conservation of the 200 bp immediately upstream of the RNA CAP site. This region contains nucleotide stretches matching with consensus sequences recognized by transcription factors, including NF-KB, CREB and NF-IL6. A potential AP-1 binding site is found 284 nucleotides upstream of the RNA CAP site. The bovine IL-6 gene promoter cloned upstream of the bacterial chloramphenicol acetyl transferase (CAT) gene was shown to be active in bovine and ovine cells.
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PMID:Nucleotide sequence of the bovine interleukin-6 gene promoter. 145 13

The events in interleukin-6 (IL-6) signal transduction leading to primary response gene activation were analyzed in murine B-cell hybridoma and plasmacytoma cells which require IL-6 for growth. IL-6 stimulation of IL-6-deprived cells resulted in the rapid and transient tyrosine phosphorylation of a 160-kDa cellular protein (p160). This was followed by the highly selective induction of two primary response genes, junB/AP-1 transcription factor and TIS11. junB and TIS11 inductions were unaffected by cycloheximide, suggesting that posttranslational modifications accounted for their activation. Activation of junB and TIS11 transcription required rapid tyrosine kinase activity as well as a different protein kinase activity sensitive to the potent kinase inhibitor, H7, and activated following p160 tyrosine phosphorylation. This H7-sensitive kinase appears to be distinct from any well-characterized protein kinase-second messenger system. On the basis of these findings, we propose that IL-6-induced signal transduction proceeds through a novel protein kinase cascade which activates junB and TIS11 gene transcription.
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PMID:Interleukin-6 signals activating junB and TIS11 gene transcription in a B-cell hybridoma. 170 5

Induction of differentiation to macrophages in two different clones of myeloid leukemic cells by the hematopoietic regulatory proteins interleukin-6 (IL-6), or by granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3), is shown to be associated with sustained accumulation of c-jun, jun-B, and c-fos mRNA that code for proteins that form complexes that are transcription factors (AP-1). In one but not in the other of these leukemic clones, differentiation is also associated with sustained accumulation of mRNA for the putative transcription factor zif/268. The results indicate that differentiation of myeloid cells by normal hematopoietic regulatory proteins is associated with induction of sustained elevated levels of mRNA for transcription factors that can regulate and maintain gene expression in the differentiation program, and that zif/268 gene expression is not essential for differentiation to macrophages.
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PMID:Induction of genes for transcription factors by normal hematopoietic regulatory proteins in the differentiation of myeloid leukemic cells. 224 2

Interleukin-6 (IL-6) is a major systemic alarm signal that indicates the occurrence of tissue damage. The IL-6 gene is induced in various cell types by serum, inflammation-associated cytokines, viruses, and second-messenger agonists. There is an overall functional similarity between IL-6 and c-fos promoters, since transfection of excess amounts of either promoter DNA into intact HeLa cells modulates the function of the heterologous promoter construct. Furthermore, the transcription regulatory factor Fos transrepresses both the IL-6 and c-fos promoters. The 115-base pair (bp) region from -225 to -111 in the IL-6 5'-flanking region, which shares nucleotide sequence similarity with the c-fos serum response (SRE) and adjacent AP-1-like (the CGTCA motif) elements, confers responsiveness to several reagents, including serum, forskolin, and phorbol ester, upon the heterologous herpesvirus thymidine kinase (TK) promoter. In gel shift assays using nuclear extracts from HeLa cells, the 115-bp IL-6 enhancer formed several complexes that (i) were increased when extracts from induced HeLa cells were used and (ii) were inhibited most efficiently by the fos E DNA fragment (-700 to -100) and by c-fos oligonucleotides containing an intact AP-1-like site (the CGTCA motif). The 23-bp oligonucleotide designated AR1 from within the IL-6 enhancer region (-173 to -151) contains a CGTCA motif and bound nuclear proteins that also associated with c-fos oligonucleotides containing either an intact SRE or AP-1-like site. A single copy of AR1 inserted upstream of the herpesvirus TK promoter rendered this heterologous promoter inducible by IL-1 alpha, tumor necrosis factor, and serum as well as by activators of the protein kinase A (forskolin) and protein kinase C (phorbol ester) signal transduction pathways. Mutations in the AP-1-like site within AR1 (CGTCA----GTTCA) decreased inducibility of the chimeric IL-6/TK/chloramphenicol acetyltransferase gene by phorbol ester and by forskolin but not by serum, IL-1 alpha, or tumor necrosis factor. These data not only show that the AR1 segment from within the IL-6 enhancer binds nuclear proteins that also bind to c-fos regulatory elements but also demonstrate that a single copy of this 23-bp element is functionally sufficient to confer responsiveness to a variety of inducers and thus define a multiple-response element.
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PMID:A multiple cytokine- and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. 251 37

Tumour necrosis factor-alpha (TNF-alpha) is secreted by macrophages in response to inflammation, infection and cancer. Sublethal doses of recombinant TNF-alpha to rats causes cachexia, anaemia and inflammation. TNF-alpha plays a major part in tissue inflammation and remodelling by stimulating production of collagenase. Cellular responses to TNF-alpha are initiated by binding to high-affinity cell surface receptors. TNF-alpha then profoundly affects gene regulation, stimulating the fos, myc, interleukin-1 and interleukin-6 genes and inhibiting the type I collagen gene. Here we demonstrate that TNF-alpha also stimulates collagenase gene transcription; this stimulation is mediated by an element of the gene that is responsive to the transcription factor AP-1, the major component of which (jun/AP-1) is encoded by the jun gene; and that TNF-alpha stimulates prolonged activation of jun gene expression. This prolonged induction of jun contrasts with its transient activation by the phorbol ester TPA and provides a physiological example of the ability of jun/AP-1 to stimulate its own transcription. This may be a key mechanism for mediating at least some of the biological effects of TNF-alpha.
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PMID:Prolonged activation of jun and collagenase genes by tumour necrosis factor-alpha. 253 68

Interleukin-6 (IL-6) is a proinflammatory cytokine which also acts as a growth factor for some murine hybridomas (7TD1) or human myelomas (U266). We demonstrate that elevation of cAMP cellular content inhibits IL-6-stimulated cell growth, by blocking cells mainly in G1 phase. This inhibition is associated with increased expression of the Fos family protein Fra-2. Treatment of cells with 8Br-cAMP results in increased DNA-binding activity of two distinct AP-1 complexes; JunD/Fra-2 and JunB/Fra-2, and also in elevated AP-1 transactivation. When 8Br-cAMP is withdrawn from the medium, cells enter S phase and Fra-2 protein levels and AP-1 DNA-binding activity decrease to their basal value indicating that a temporally correlation exists between the 8Br-cAMP-mediated induction of JunD/Fra-2 AP-1 complex and the 7TD1 and U266 cell growth inhibition.
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PMID:Cyclic AMP stimulates a JunD/Fra-2 AP-1 complex and inhibits the proliferation of interleukin-6-dependent cell lines. 756 66

In the present study, the distal part of the 5'-flanking region of the rainbow trout metallothionein-A promoter was sequenced in order to identify cis-acting regulatory elements. Analysis of this sequence combined with that previously reported for the 5'-flanking region directly proximal to the start of transcription revealed several putative regulatory sequences. In total, six metal-responsive elements (MREs) were identified; these sequences were organised into two clusters, one containing two copies of MRE and located close to the predicted TATA box sequence, and a second consisting of four MREs and lying 500-700 bp upstream from the start of transcription. In addition, the 5'-flanking region contained sequences sharing high similarity with the activator protein 1 consensus sequence as well as one nuclear-factor-interleukin-6-responsive element. Functional analysis of the promoter was performed by introducing deletion mutants of the 5'-flanking region into the vector pGL-2, directly upstream from the luciferase reporter gene. Both MRE clusters were needed for maximal metal inducibility in both rainbow trout hepatoma (RTH-149) and human hepatoblastoma (Hep G2) cell lines. Furthermore, the distal region was found to be functional in promoting gene transcription following exposure of RTH-149 cells to hydrogen peroxide.
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PMID:Structural and functional analysis of the rainbow trout (Oncorhyncus mykiss) metallothionein-A gene. 760 Nov 21

Epidemiologic data indicate the crucial role of chronic hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development. On the molecular level, HBV sequences are frequently integrated in hepatocellular DNA. However, in contrast to the woodchuck model, in which specific HBV-DNA integration is detectable in most cases, insertional (in-) activation of cellular genes seems to be a rare event in man. The recent discovery of transactivating functions exerted by HBx and truncated HBs(urface) proteins supports the notion that transactivation of cellular gene expression could be relevant to hepatocarcinogenesis. HBV transactivator sequences are present in 81% (21/26) of HCC tissues or hepatoma-derived cell lines. At least one transactivator protein was functional in all cases investigated so far. The 16.5-kDa HBx transactivator has been shown to stimulate gene expression from various cellular target sequences. In vitro, HBx displays oncogenic potential. A second type of transactivator is encoded in the preS/S region of HBV. In contrast to HBx, HBs transactivators require carboxyterminal truncation to gain their transactivating function. Unlike full-length M(iddle)HBs, the truncated MHBst is retained in the endoplasmic reticulum and not secreted into the surrounding medium. Cellular gene expression is stimulated by regulatory elements of the human proto-oncogenes c-fos and c-myc, as well as by the hepatic acute-phase interleukin-6 gene. Synthetic binding sites for the transcription factors NF-kappa B, AP-1, AP-2, SRE, and Sp1 render minimal promoters activatable. NF-kappa B-mediated transactivation by MHBst can be suppressed by radical scavenging antioxidants, indirectly suggesting that reactive oxygen intermediates are involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. 760 73

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


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