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)

Acute-phase reactants are liver proteins whose synthesis is positively or negatively regulated during inflammation. The main mediators of this phenomenon are glucocorticoids and interleukin-6 (IL-6), a pleiotropic cytokine that also controls hematopoiesis. Functional analysis of several acute-phase reactant promoter regions has identified two major DNA motifs used by IL-6-regulated genes. The first one corresponds to a CTGG(G/A)AA sequence, and the other is a binding site for members of the C/EBP family of nuclear proteins. We have previously shown that the human beta fibrinogen (beta Fg) promoter contains an IL-6-responsive region, located between bp -150 and -67 (P. Huber, M. Laurent, and J. Dalmon, J. Biol. Chem. 265:5695-5701, 1990). In this study, using DNase I footprinting, mobility shift assays, and mutagenesis, we demonstrate that at least three subdomains of this region are necessary to observe a full response to IL-6. The most distal contains a CTGGGAA motif, and its mutation inhibits IL-6 stimulation. Another, which is able to interact with several distinct nuclear proteins, among them members of the C/EBP family, is dispensable for IL-6 induction but plays an important role in the constitutive expression of beta Fg. Finally, a proximal hepatocyte nuclear factor 1 binding site, already described as the major determinant of beta Fg tissue-specific expression, is also required for IL-6 stimulation. These results indicate a complex interplay between nuclear proteins within the beta Fg IL-6-responsive region and suggest a tight functional coupling between the tissue-specific and inducible elements.
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PMID:The human beta fibrinogen promoter contains a hepatocyte nuclear factor 1-dependent interleukin-6-responsive element. 842 85

The nuclear signaling by the pleiotropic cytokine interleukin-6 (IL-6) has been investigated in human embryonal carcinoma cells and T cells. We show that Oct-1, a ubiquitously expressed octamer-binding protein known to be regulated posttranslationally, can also be regulated at the levels of mRNA and protein synthesis by IL-6 and by retinoic acid (RA) in human embryonal carcinoma cells. NF-IL6, an IL-6-inducible transcription factor of the C/EBP family, can confer this regulation and is itself regulated by both signals. The abundance and the molar ratios of the three forms of NF-IL6, corresponding to peptides initiated in frame from different AUGs of the same NF-IL6 mRNA species, are regulated by IL-6 and by RA. These results suggest that the two signal transduction pathways overlap in human embryonal carcinoma cells and that Oct-1 may be downstream of NF-IL6 in the shared regulatory cascade. Enhanced Oct-1 synthesis correlates with one of the functions of Oct-1, i.e., stimulation of adenovirus DNA replication. This provides an example of a possible functional consequence of IL-6 and RA signaling that is mediated by NF-IL6 and Oct-1 regulation.
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PMID:Convergent regulation of NF-IL6 and Oct-1 synthesis by interleukin-6 and retinoic acid signaling in embryonal carcinoma cells. 845 26

We investigated the expression of the human DNA topoisomerase I (hTOP1) gene in HeLa cells and in adenovirus-transformed 293 cells. A highly conserved proximal promoter element is essential for hTOP1 promoter activity in HeLa cells but not in 293 cells. This correlates with the presence of specific promoter-binding proteins in HeLa cells and their absence in 293 cells. We identified the HeLa binding protein by screening a cDNA expression library with the specific promoter site as a probe and demonstrate now that the activating protein is identical to the nuclear factor for interleukin-6 expression (NF-IL6), a member of the C/EBP family of transcription factors. Overexpression of NF-IL6 strongly stimulates hTOP1 promoter activity in HeLa cells, suggesting that NF-IL6 is a major hTOP1-regulating protein. Because of the presence of adenovirus protein E1A, 293 cells express the hTOP1 gene more efficiently than HeLa cells but do not contain NF-IL6 activity. E1A activation of the hTOP1 promoter is suppressed by NF-IL6 overexpression. This result supports previous observations concerning a functional interaction between viral protein E1A and NF-IL6. Finally, we show that hTOP1 gene expression in differentiating macrophages is correlated with the synthesis of NF-IL6-specific mRNA.
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PMID:The human topoisomerase I gene promoter is regulated by NF-IL6. 852 27

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

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

A variety of injuries, such as bacterial infection or ischemic tissue necrosis, induce systemic acute phase reaction expressed as fever, leukocytosis, release of several hormones, activation of clotting, complement and kinin forming pathways, and drastic increase of synthesis of certain plasma proteins. The reaction is triggered by 'alarm molecules', including free radicals, which activate several stress-sensitive protein kinases (ERK, p38, JNK) in macrophages and other responsive cells. These kinases phosphorylate, usually in a multi-step cascade, transcription factors belonging primarily to C/EBP, NF-kappa B and AP-1 families. Active transcription factors after translocation to nucleus interact with responsive elements in the gene promoters of acute-phase cytokines: tumor necrosis factor-alpha, interleukin-1 and interleukin-6. Enhanced transcription of these genes is usually followed by rapid translation and precursor protein processing leading to the release of biologically active cytokines. Fine tuning of the acute phase response appears to be regulated at all stages: primary signals, kinase cascades, transcription factors, mRNA stability and translation, cytokine precursor processing, secretion and bioavailability. This makes possible designing of specific inhibitors of cytokine synthesis as potential therapeutic drugs.
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PMID:Initiation of acute phase response and synthesis of cytokines. 895 Jan 92

Human immunodeficiency virus type 1 (HIV-1) infection is associated with severe psoriasis, B cell lymphoma, and Kaposi's sarcoma. A deregulated production of interleukin-6 (IL6) has been implicated in the pathogenesis of these diseases. The molecular mechanisms underlying the abnormal IL6 secretion of HIV-1-infected cells may include transactivation of the IL6 gene by HIV-1. Here we report the molecular mechanisms of Tat activity on the expression of the IL6 gene. By using 5' deletion mutants of pIL6Pr-CAT and using IL6:HIV-1-LTR hybrid constructs where discrete regions of the IL6 promoter replaced the TAR sequence in HIV-1 LTR, we identified a short sequence of the 5'-untranslated region of the IL6 mRNA that is required for Tat to trans-activate the IL6 promoter. This sequence acquires a stem-loop structure and includes a UCU sequence that binds to Tat and is necessary for full trans-activation. In addition, we provide the evidence that Tat can function by enhancing the CAAT enhancer-binding protein (C/EBP) DNA binding activity and is able to complex with in vitro translated C/EBPbeta, which is a major mediator of IL6 promoter function. By using the yeast two-hybrid system and immunoprecipitation, we observed that the interaction of Tat with C/EBP proteins also occurred in vivo. The data are consistent with the possibility that Tat may function on heterologous genes by interacting with RNA structures possibly present in a large number of cellular and viral genes. In addition, Tat may function by protein-protein interactions, leading to the generation of heterodimers with specific transcription factors.
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PMID:HIV-1 Tat induces the expression of the interleukin-6 (IL6) gene by binding to the IL6 leader RNA and by interacting with CAAT enhancer-binding protein beta (NF-IL6) transcription factors. 916 58

Interleukin-6 (IL-6) is a multifunctional cytokine thought to be a key factor in post-menopausal osteoporosis, given its ability to induce osteoclast maturation and its down regulation by estrogens. We have previously shown that the effects of TNFalphaand estradiol on the human IL-6 promoter were dependent on a region of the promoter containing a C/EBP site and a NF-kappaB site. To define the molecular mode of action of estrogens, we performed gel shift assays with this DNA fragment as a probe, and nuclear extracts from TNFalpha-induced HeLa, MCF7 and Saos2 cells. Several induced complexes specifically bound the probe. The use of various competitor DNA suggested that most of the complexes detected contained NF-kappaB factors, and that C/EBP site binding factors were important for the overall binding to the probe. Addition of in vitro translated human estrogen receptor (hER) impaired the binding of three complexes in HeLa cells and two complexes in MCF7 and Saos2 cells. Competition experiments suggested that the NF-kappaB site was necessary for the effect of hER. The use of antisera against NF-kappaB and C/EBP proteins showed that the target complexes of hER contained the c-rel proto-oncogene product and to a lesser extent, the RelA protein. Taken together, these data show that hER impairs TNFalphainduction of IL-6 by preventing c-rel and, to a lesser extent, RelA proteins binding to the NF-kappaB site of the IL-6 promoter.
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PMID:Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-kappaB site. 917 Oct 95

CAAT/enhancer binding proteins (C/EBP) are a family of transcription factors that mediates adipocyte differentiation and the regulation of genes expressed in immune responses and inflammation, such as interleukin-6 (IL-6), IL-8, and granulocyte colony-stimulating factor (G-CSF). We investigated the role of C/EBPbeta (NF-IL6) in the generation of bone marrow B lymphocytes by taking advantage of C/EBPbeta-/- mice. We found that the expansion of bone marrow (BM) B lymphocytes was impaired in long-term lymphoid cultures from C/EBPbeta-/- mice. Consistent with this finding, the number of BM B cells was decreased in C/EBPbeta-/- mice. Both the levels of IL-7 gene expression and bioactive IL-7 from BM stromal cells were decreased in C/EBPbeta-/- mice. Furthermore, the proliferative responsiveness of BM B-cell precursors to IL-7 was also reduced as compared to wild-type mice, indicating that C/EBPbeta is required for the generation of BM B cells induced by IL-7. Accordingly, IL-7 stimulates the C/EBPbeta DNA-binding activity of normal BM pre-B lymphocytes as well as of 70Z/3 pre-B cells. These results point to C/EBPbeta as a critical signaling molecule in BM B lymphopoiesis.
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PMID:Impaired generation of bone marrow B lymphocytes in mice deficient in C/EBPbeta. 920 49

We previously reported that a mutation in a 3' enhancer region of the alpha1-antitrypsin (AAT) gene is associated with chronic obstructive airways disease (COAD). During the acute-phase response the plasma concentration of AAT increases approximately 3-fold and this effect is mediated primarily by interleukin-6 (IL-6). We demonstrate, by transfection of Hep G2 cells, that the AAT gene contains at least two enhancers, one at the 5' end of the gene which is dominant under basal conditions, and another at the 3' end of the gene which exhibits weak basal activity. However, both enhancers must be present to modulate the IL-6-induced response which is diminished as a consequence of the 3' enhancer mutation. These results suggest that the 3' enhancer modulates the IL-6 response through an interaction with the 5' enhancer. The mutation occurs at a DNA binding site for the ubiquitous transcription factor octamer-1 (Oct-1) and results in a loss of cooperativity between Oct-1 and the tissue-specific transcription factor, NF-IL6 (C/EBPbeta), a member of the C/EBP family of transcription factors. NF-IL6 is a key transcription factor for a major pathway through which IL-6 mediates its effects. These observations provide a novel mechanism for a diminished IL-6-induced response.
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PMID:Mutation in an alpha1-antitrypsin enhancer results in an interleukin-6 deficient acute-phase response due to loss of cooperativity between transcription factors. 943 1


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