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)

Coagulation Factor VIII is an acute phase protein in humans that has recently been shown to be transcriptionally responsive to interleukin-6. In this study, we have demonstrated that the human Factor VIII promoter is activated in cultured hepatocytes exposed to bacterial lipopolysaccharide (LPS). Deletion analysis has narrowed the LPS-responsive element of the Factor VIII promoter to a small region which contains two C/EBP binding sites and an adjacent NFkappaB binding site. Mutation of the downstream C/EBP site reduces LPS-responsiveness by approximately 50%, while mutation of the NFkappaB binding site completely eliminates LPS-responsiveness. While binding of C/EBPbeta and NFkappaB is still observed in gel retardation studies using acute phase nuclear extracts and a probe containing mutations to the downstream C/EBP site, neither NFkappaB nor C/EBP appear to bind to a probe in which the NFkappaB site has been mutated. Conservation of this region of the Factor VIII promoter in species which exhibit an increase in Factor VIII levels in response to inflammatory stimuli suggests that these transcription factor binding sites are important for normal regulation of the Factor VIII gene under conditions of stress.
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PMID:The Factor VIII acute phase response requires the participation of NFkappaB and C/EBP. 1095 92

Secreted phospholipases A(2) is a family of small molecular weight and calcium-dependent enzymes of which the members list is presently growing. Among these enzymes, the synovial type IIA and the type V phospholipases A(2) are involved in inflammation. Although their actual mechanism is still a subject of debate, new therapeutic strategies can result from the knowledge of the regulations of their gene expression. The human genes of the type IIA and type V phospholipases A(2) are located on the chromosome 1 at close positions and transcribed in reverse orientations. These genes can therefore be regulated by common elements but only the regulation of the type IIA phospholipase A(2) gene expression has been extensively studied. Pro-inflammatory cytokines upregulate while the growth factors downregulate the type IIA phospholipase A(2) gene expression. Interleukin-6 and interleukin-1beta exert their effects at least partially at the transcriptional level. The transcriptional regulation of the type IIA phospholipase A(2) gene is cell- and species-specific. The activity of the human promoter is controlled by the CAAT-enhancer binding protein (C/EBP) factors while that of the rat promoter is regulated by nuclear factor kappaB (NF-kappaB) and C/EBPs. Furthermore, the human promoter is constitutively repressed in hepatocytes by single strand DNA binding proteins whose effects are relieved by C/EBP factors while the glucocorticoid receptor interacts with C/EBPs in chondrocytes to achieve full basal and interleukin-1beta-stimulated transcription activity. Other factors like CTF/NF1 and Sp1 might be involved in the regulation of both the rat and human promoter. Peroxisome proliferator-activated receptors could contribute to the stimulation of the rat promoter by NF-kappaB in vascular smooth muscle cells. The study of the coactivators and coinhibitors associated to these transcription factors will give a better understanding of the diversity and complexity of the transcriptional regulations of the type IIA phospholipase A(2) gene.
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PMID:Transcriptional regulation of inflammatory secreted phospholipases A(2). 1108 Jun 84

Recent observations have shown two CCAAT/enhancer binding protein (C/EBP) binding sites to be critically important for efficient human immunodeficiency virus type 1 (HIV-1) replication within cells of the monocyte/macrophage lineage, a cell type likely involved in transport of the virus to the brain. Additionally, sequence variation at C/EBP site I, which lies immediately upstream of the distal nuclear factor kappa B site and immediately downstream of a binding site for activating transcription factor (ATF)/cyclic AMP response element binding protein (CREB), has been shown to affect HIV-1 long terminal repeat (LTR) activity. Given that C/EBP proteins have been shown to interact with many other transcription factors including members of the ATF/CREB family, we proceeded to determine whether an adjacent ATF/CREB binding site could affect C/EBP protein binding to C/EBP site I. Electrophoretic mobility shift analyses indicated that selected ATF/CREB site variants assisted in the recruitment of C/EBP proteins to an adjacent, naturally occurring, low-affinity C/EBP site. This biophysical interaction appears to occur via at least two mechanisms. First, low amounts of CREB-1 and C/EBP appear to heterodimerize and bind to a site consisting of a half site from both the ATF/CREB and C/EBP binding sites. In addition, CREB-1 homodimers bind to the ATF/CREB site and recruit C/EBP dimers to their cognate weak binding sites. This interaction is reciprocal, since C/EBP dimer binding to a strong C/EBP site leads to enhanced CREB-1 recruitment to ATF/CREB sites that are weakly bound by CREB. Sequence variation at both C/EBP and ATF/CREB sites affects the molecular interactions involved in mediating both of these mechanisms. Most importantly, sequence variation at the ATF/CREB binding site affected basal LTR activity as well as LTR function following interleukin-6 stimulation, a treatment that leads to increases in C/EBP activation. Thus, HIV-1 LTR ATF/CREB binding site sequence variation may modulate cellular signaling at the viral promoter through the C/EBP pathway.
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PMID:Interaction between CCAAT/enhancer binding protein and cyclic AMP response element binding protein 1 regulates human immunodeficiency virus type 1 transcription in cells of the monocyte/macrophage lineage. 1116 Jun 83

Transcription factors belonging to the CCAAT-enhancer binding protein (C/EBP) family play key roles in the regulation of genes implicated in the control of growth, differentiation, metabolism, and inflammation. The recent limited studies on the promoter regions of C/EBP genes, particularly C/EBPalpha, have indicated the potential existence of species-specific regulatory mechanisms. It is therefore essential that the promoter regions of different C/EBP genes from a wide range of species are investigated in detail. As an important step toward this goal, we report here the characterization of the Xenopus laevis C/EBPbeta gene promoter. Sequence analysis showed that the 1.6-kb promoter region contained putative binding sites for several transcription factors that have previously been implicated in the regulation of the C/EBPs, including C/EBP, CREB, Myb, STAT, and USF. The -288/+91 promoter region was capable of directing high levels of expression in the hepatoma Hep3B cell line. In addition, this minimal promoter could be autoregulated by both C/EBPalpha and C/EBPbeta and activated by lipopolysaccharide, interleukin-6 and CREB. These results therefore demonstrate that several aspects of C/EBPbeta regulation in mammals have been highly conserved in amphibians. However, a comparison of C/EBPbeta gene promoters characterized to date does indicate the existence of species-specific differences in autoregulation.
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PMID:Molecular characterization of the Xenopus CCAAT-enhancer binding protein beta gene promoter. 1144 61

Nuclear factor-interleukin-6 (NF-IL6), a human transcription factor of the CCAAT-box/enhancer binding protein (C/EBP) family, is widely implicated as a "master regulator" of hepatic acute-phrase response and inflammatory cytokine gene expression. NF-IL6 contains, at its N-terminus, an alanine- and proline-rich transactivation domain, followed at the C-terminus by a basic domain-leucine zipper (bZIP) DNA-binding motif. Understanding how the NF-IL6 transcription factor interacts with DNA is fundamental to its role as a transactivator because sequence-specific DNA-binding is prerequisite to promoter activation. We review our findings on the identification of the minimal "core" DNA-binding domain and the discovery of a novel bZIP element that influences DNA-binding kinetics. Manipulation of this domain allows for design of molecules that can be used as competitive antagonists or targeted delivery of molecules to selected regions of the eukaryotic genome.
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PMID:The Basic Amino Acid-Rich DNA-Binding Element of the NF-IL6 Transcription Factor Contains Two Functionally Distinct Subdomains. 1185 44

Hypertension is a serious health problem in Western society, in particular for the African-American population. Although previous studies have suggested that the angiotensinogen (AGT) gene locus is involved in human essential hypertension, the molecular mechanisms involved in hypertension in African-Americans remain unknown. We show that an A/G polymorphism at -217 in the promoter of the AGT gene plays a significant role in hypertension in African-Americans. The frequency of the -217A allele was increased significantly in African-American hypertensive subjects compared with normotensive controls. We also show that the nucleotide sequence of this region of the AGT gene promoter bound strongly to CAAT/enhancer-binding protein (C/EBP) family transcription factors when nucleoside A was present at -217. In addition, we show that reporter constructs containing the human AGT gene promoter with nucleoside A at -217 had increased basal transcriptional activity upon transient transfection in HepG2 cells compared with reporter constructs with nucleoside G at -217. Finally, we show that interleukin-6 treatment in the presence or absence of overexpressed C/EBPbeta increased the promoter activities of reporter constructs containing nucleoside A at -217 compared with reporter constructs containing nucleoside G at -217. Because the AGT gene is expressed primarily in liver and adipose tissue, and C/EBP family transcription factors play an important role in gene expression in these tissues, we propose that increased transcriptional activity of the -217A allele of the human AGT gene is associated with hypertension in African-Americans.
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PMID:Angiotensinogen gene polymorphism at -217 affects basal promoter activity and is associated with hypertension in African-Americans. 1214 90

CCAAT/enhancer-binding protein gamma (C/EBP gamma) is an ubiquitously expressed member of the C/EBP family of transcription factors that has been shown to be an inhibitor of C/EBP transcriptional activators and has been proposed to act as a buffer against C/EBP-mediated activation. We have now unexpectedly found that C/EBP gamma dramatically augments the activity of C/EBP beta in lipopolysaccharide induction of the interleukin-6 and interleukin-8 promoters in a B lymphoblast cell line. This activating role for C/EBP gamma is promoter-specific, neither being observed in the regulation of a simple C/EBP-dependent promoter nor the TNF alpha promoter. C/EBP gamma activity also shows cell-type specificity with no activity observed in a macrophage cell line. Studies with chimeric C/EBP proteins implicate the formation of a heterodimeric leucine zipper between C/EBP beta and C/EBP gamma as the critical structural feature required for C/EBP gamma stimulatory activity. These findings suggest a unique role for C/EBP gamma in B cell gene regulation and, along with our previous observation of the ability of C/EBP basic region-leucine zipper domains to confer lipopolysaccharide inducibility of interleukin-6, suggest that the C/EBP leucine zipper domain has a role in C/EBP function beyond allowing dimerization between C/EBP family members.
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PMID:C/EBP gamma has a stimulatory role on the IL-6 and IL-8 promoters. 1217 65

The ILRE (interleukin response element) contained within the promoter of the interleukin-6 (IL-6) gene is defined as the site recognized by the p65 NF-kappaB transcriptional activator and is crucial for activation of the IL-6 gene. The region of the promoter containing the ILRE is complex containing a CCAAT enhancer-binding protein (C/EBP) site immediately upstream of the ILRE, which is required for optimal activation of the IL-6 gene. Additionally, the ILRE overlaps a site that is recognized by the mammalian transcriptional repressor RBP (CBF-1), and RBP binding within the ILRE region represses activated IL-6 expression. In this study, the complexity of this region is further revealed by the identification of a second nested C/EBP site, which overlaps that of RBP and therefore also the ILRE. Optimal activation requires both the upstream and newly identified C/EBP sites in conjunction with the p65 NF-kappaB binding site. We previously reported that RBP represses IL-6 activation but does not target p65. We extend these analyses here to show that RBP binding does not occlude p65 from binding but instead directly overlaps the newly identified downstream C/EBP site, thereby impeding p65-C/EBP-mediated co-activation. This result suggests a role for RBP in the repression of other genes containing a C/EBP site that exhibits sequence overlap with the RBP site.
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PMID:Binding of C/EBP and RBP (CBF1) to overlapping sites regulates interleukin-6 gene expression. 1220 Apr 47

Turpentine-induced acute-phase (AP) response in rats is followed by transcriptional activation of the alpha2-macroglobulin (MG) gene mediated by cytokine interleukin-6 (IL-6) and glucocorticoids. Based on nucleotide sequence analysis of the alpha2-MG gene promoter regions responsive to IL-6, we postulated that binding of members of the liver-enriched CCAAT-enhancer-binding proteins (C/EBP) family of transcription factors to the type I IL-6 responsive element (IL-6RE) may participate in the transcriptional activation of this gene during AP response. Results of Western immunoblot and Northern-blot assays revealed coordinate changes in the pool levels of C/EBPalpha, -beta. and -delta protein isoforms and their genes expression in liver in response to turpentine. By means of an in vitro phosphorylation assay, South-Western blot, and selective proteolysis we have also found that only abilities of 35-kD C/EBPbeta and 27-kD C/EBPdelta to bind to the alpha2-MG gene promoter were affected by phosphorylation. Based on these data we concluded that transcriptional induction of the rat alpha2-MG gene during AP response correlates with both increased synthesis and phosphorylation-induced binding of 35-kD C/EBPbeta and 27-kD C/EBPdelta.
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PMID:DNA binding activity of C/EBPbeta and C/EBPdelta for the rat alpha2-macroglobulin gene promoter is regulated in an acute-phase dependent manner. 1222 92

Interleukin-8 (IL-8), which is a member of C-X-C chemokine subfamily, is an important activator and chemoattractant for neutrophils and has been implicated in a variety of inflammatory diseases. Numerous reports show that various cells express IL-8 mRNA and produce IL-8 protein rapidly, including monocytes, T lymphocytes, neutrophils, fibroblasts, endothelial cells and epithelial cells. The human IL-8 gene has a length of 5191 bp and contains four exons separated by three introns. It maps to human chromosome 4q12-q21. The mRNA consists of a 101 bases 5' untranslated region, an open reading frame of 297 bases, and a long 3' untranslated region of 1.2 kb. The 5' flanking region of the IL-8 gene contains potential binding sites for several nuclear factors including activated protein-1 (AP-1), activated protein-2 (AP-2), nuclear factor-gene binding (NF-kappa B), nuclear factor-interleukin-6 (NF-IL-6, also calls CAAT/enhancer-binding proteins, C/EBP), IFN regulatory factor-1 (IRF-1), hepatocyte nuclear factor-1 (HNF-1), and so on. IL-8 gene expression is regulated initially at the level of gene transcription. The rapid induction of IL-8 gene expression is likely mediated by latent transcription factors that bind the IL-8 promoter. AP-1 and NF-IL-6 physically interact with NF-kappa B, and functional cooperativity among these factors appears to be critical for optimal IL-8 promoter activity in different cell types. The IL-8 receptor (IL-8R) is a dimeric glycoprotein consisting of a 59 KDa and a 67 KDa subunit. It has been given the name CDw128. It is expressed in many different cell types including those not responding to IL-8. The receptor density is approximately 20,000/cell in neutrophils, 1,040/cell in monocytes, and 300/cell in T-lymphocytes. The IL-8R is a member of the family of G-protein-coupled receptors. There are at least two different IL-8 receptor types (CXCR1 and CXCR2). The activities of IL-8 are not species-specific. IL-8 affects the adhesion of neutrophils to the endothelium and induces the transendothelial migration of neutrophils. IL-8 also exhibits in vitro chemotactic activities against of T-lymphocytes and basophils. IL-8 gene expression can be regulated by fluid shear stress, which may play an important role in the genesis and development of both inflammation and arterosclerosis.
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PMID:[The study on the interleukin-8 (IL-8)]. 1256 82

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