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Query: UNIPROT:P06889 (Mol)
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We have previously reported on the presence of a CArG motif at -100 in the Rous sarcoma virus long terminal repeat which binds an avian nuclear protein termed enhancer factor III (EFIII) (A. Boulden and L. Sealy, Virology 174:204-216, 1990). By all analyses, EFIII protein appears to be the avian homolog of the serum response factor (SRF). In this study, we identify a second CArG motif (EFIIIB) in the Rous sarcoma virus long terminal repeat enhancer at -162 and show only slightly lower binding affinity of the EFIII/SRF protein for this element in comparison with c-fos serum response element (SRE) and EFIII DNAs. Although all three elements bind the SRF with similar affinities, serum induction mediated by the c-fos SRE greatly exceeds that effected by the EFIII or EFIIIB sequence. We postulated that this difference in serum inducibility might result from binding of factors other than the SRF which occurs on the c-fos SRE but not on EFIII and EFIIIB sequences. Upon closer inspection of nuclear proteins which bind the c-fos SRE in chicken embryo fibroblast and NIH 3T3 nuclear extracts, we discovered another binding factor, SRE-binding protein (SRE BP), which fails to recognize EFIII DNA with high affinity. Competition analyses, methylation interference, and site-directed mutagenesis have determined that the SRE BP binding element overlaps and lies immediately 3' to the CArG box of the c-fos SRE. Mutation of the c-fos SRE so that it no longer binds SRE BP reduces serum inducibility to 33% of the wild-type level. Conversely, mutation of the EFIII sequence so that it binds SRE BP with high affinity results in a 400% increase in serum induction, with maximal stimulation equaling that of the c-fos SRE. We conclude that binding of both SRE BP and SRF is required for maximal serum induction. The SRE BP binding site coincides with the recently reported binding site for rNF-IL6 on the c-fos SRE. Nonetheless, we show that SRE BP is distinct from rNF-IL6, and identification of this novel factor is being pursued.
Mol Cell Biol 1992 Oct
PMID:Maximal serum stimulation of the c-fos serum response element requires both the serum response factor and a novel binding factor, SRE-binding protein. 132 62

A quantitative polymerase chain reaction (PCR) using an internal control (Standard) RNA was developed for precise quantitation of human cytokine mRNA. The target mRNA and internal control were simultaneously reverse transcribed and co-amplified using the same set of primers. The amount of specific target mRNA is then quantitated by extrapolating against the standard curve generated with the internal standard. The internal control RNA consisted of linearly connected sequences of the 5' primers of multiple cytokine genes followed by the complementary sequences to their 3' primers in the same order. This structure of the internal standard enables one to use the same internal standard for quantitating multiple cytokine mRNAs. Using this approach, we estimated the induced levels of cytokine mRNA, IL2, IL6, and TNF-alpha to be 2.8 x 10(6), 2.4 x 10(5) and 3.4 x 10(8) molecules per 1.0 microgram total cellular RNA of Jurkat, THP-1 and HL 60 cells, respectively. Comparable values were obtained when quantitation experiments were done on another batch of THP-1 and HL-60 total cellular RNA. The excellent sensitivity and reproducibility makes this approach a valuable one in following changes in cytokine gene expression in wide variety of conditions, both in vivo and in vitro.
Mol Immunol 1992 Oct
PMID:Use of quantitative polymerase chain reaction to quantitate cytokine messenger RNA molecules. 152 93

We have shown previously that transforming growth factor beta 1 (TGF-beta 1) is antimitotic for human fetal adrenal (HFA) cells in vitro and that this effect can be partially blocked by adrenocorticotropic hormone (ACTH). In the present study, we sought to determine whether ACTH might interfere with TGF-beta 1 action by means of reducing TGF-beta 1 binding to adrenal cells. We incubated adrenal cells with 50 pM 125I-labeled TGF-beta 1 for 15 min to 3 h at 4 degree C and found that the binding of 125I-labeled TGF-beta 1 increased with time and could be inhibited in a dose-dependent manner by non-labeled TGF-beta 1 (0.05-10 nM), but not with other relevant cytokines: IL6, TNF alpha,IGF-I, IGF-II, TGF-alpha, and EGF. Pretreatment of HFA cells with ACTH (0.009-900 nM) for 4-24 h significantly increased specific 125I-labeled TGF-beta 1 binding compared to that in untreated cells; maximal increases in binding were achieved with 0.9 nM ACTH. This effect of ACTH could be mimicked by treatment of adrenal cells with dibutyryl cAMP (1 mM) or forskolin (10 microM). Scatchard analysis of data from ACTH-treated cells suggest the presence of two populations of TGF-beta 1 binding sites with different affinity and capacity of binding for the ligand.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Apr 01
PMID:Receptor binding of transforming growth factor-beta by human fetal adrenal cells. 766 78

The cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) are released by mononuclear phagocytes in vitro after stimulation with mycobacteria and are considered to mediate pathophysiologic events, including granuloma formation and systemic symptoms. We demonstrated that the Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM) is a very potent inducer of IL-1 beta gene expression in human monocytes and investigated the mechanism of this effect. We localized the LAM-, lipopolysaccharide (LPS)-, and TNF-alpha-inducible promoter activity to a -131/+15 (positions -131 to +15) DNA fragment of the IL-1 beta gene by deletion analysis and chloramphenicol acetyltransferase assay. Within this DNA fragment, there were two novel 9-bp motifs (-90/-82 and -40/-32) with high homology to the nuclear factor-IL6 (NF-IL6) binding site. Site-directed mutagenesis demonstrated that the two NF-IL-6 motifs could be independently activated by LAM, LPS, or TNF-alpha and that they acted in an orientation-independent manner. DNA mobility shift assay revealed specific binding of nuclear protein(s) from LAM-, LPS-, or TNF-alpha-stimulated THP-1 cells to the NF-IL6 motifs. We conclude that the two NF-IL6 sites mediate induction of IL-1 beta in response to the stimuli LAM, LPS, and TNF-alpha.
Mol Cell Biol 1993 Jun
PMID:Regulation of the interleukin-1 beta (IL-1 beta) gene by mycobacterial components and lipopolysaccharide is mediated by two nuclear factor-IL6 motifs. 768 3

The Burkitt's lymphoma receptor 1 (BLR1) identified initially in Burkitt lymphoma cells has been the first member of the superfamily of G-protein-coupled receptors with a lymphocyte specific expression pattern. BLR1 shows significant relationship to receptors for chemokines (IL-8, MIP-1 beta) and neuropeptides. The gene encoding the murine homologue of the human BLR1 receptor was isolated and used to study its tissue-specific expression. Blr-1 consists of two exons encoding a protein of 374 amino acid residues which shows 83% identity with the human homologue. Screening of normal tissues of adult BALB/c mice revealed that blr-1-specific RNA is detected consistently at low levels in secondary lymphatic organs. The blr-1 gene is expressed regularly and strongly in lymphomas of mature B cells but not in plasmacytomas. SCID mice deficient in the development of mature B cells have strongly reduced levels of blr-1-specific RNA in the spleen. Cytokine mediated induction (IL4, IL6) of terminal differentiation of resting B cells towards Ig-secreting plasma cells completely downregulates expression of blr-1. RNA in situ hybridization using brain sections demonstrates blr 1 transcription in the granule and Purkinje cell layer of the cerebellum. The precise delineation of the restricted expression pattern of the blr-1 gene will support the identification of its ligand and may provide a clue to understand how BLR1 exerts its biological function within the immune and nervous system.
Cell Mol Biol (Noisy-le-grand) 1994 May
PMID:Selective expression of the murine homologue of the G-protein-coupled receptor BLR1 in B cell differentiation, B cell neoplasia and defined areas of the cerebellum. 792 Jan 82

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

The acute-phase reaction is accompanied by an increase in a variety of serum proteins, named acute-phase proteins. The synthesis of these proteins is synergistically controlled by glucocorticoids and inflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha. Recently, we have cloned nuclear factor-IL-6 (NF-IL6), a transcription factor that activates the IL-6 gene, and have demonstrated its involvement in the expression of acute-phase-protein genes. We report here an analysis of the molecular mechanisms by which inflammatory cytokines and glucocorticoid act synergistically to activate expression of the rat alpha 1-acid glycoprotein (AGP) gene. We found that NF-IL6 and ligand-activated rat glucocorticoid receptor acted synergistically to transactivate the AGP gene and that maximal transcriptional activation of the AGP gene required expression of both intact NF-IL6 and rat glucocorticoid receptor. Surprisingly, however, transcriptional synergism was still observed even when one of the two factors lacked either its DNA-binding or transcriptional-activation function. We present evidence for a direct protein-protein interaction between these two distinct transcription factors and propose that this may be responsible for the synergistic activation of the rat AGP gene.
Mol Cell Biol 1993 Mar
PMID:A nuclear factor for interleukin-6 expression (NF-IL6) and the glucocorticoid receptor synergistically activate transcription of the rat alpha 1-acid glycoprotein gene via direct protein-protein interaction. 844 18

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.
Mol Cell Biol 1995 Dec
PMID:The human topoisomerase I gene promoter is regulated by NF-IL6. 852 27

The study investigated the changes in individual molecular species in PE and the effects of a variety of dietary fats with varying proportions of saturated and unsaturated fatty acids on membrane composition, eicosanoid production and cytokine production in thioglycollate-elicited rat macrophages. The data obtained indicates that the greatest degree of modulation by dietary fats on cytokine production was observed after 8 weeks feeding and at this time, the total diacyl species containing linoleic acid (18:2 n-6) and arachidonic acid (20:4 n-6) at the sn-2 position related in a curvilinear fashion to total 18:2 n-6 intake and that IL1 and IL6 production related in a curvilinear fashion to the total diacyl species with 20:4 and 18:2 at the sn-2 position. After 4 weeks of feeding, fish and olive oils enhanced production of IL6 and LTB4, however, while IL1 production, after 8 weeks of dietary treatment, was greatest from macrophages of animals fed corn and olive oils, PGE2 production was greatest in the former group and LTB4 production in the latter. Thus an eicosanoid effect may explain the modulatory influence of olive oil and IL1 production but, cannot explain the effect of corn oil on production of the cytokine. The data from the present study provides some insight into how dietary fats could provide therapy for conditions in which inflammatory cytokines are implicated.
Mol Cell Biochem 1996 Dec 20
PMID:The relationship between altered membrane composition, eicosanoids and TNF-induced IL1 and IL6 production in macrophages of rats fed fats of different unsaturated fatty acid composition. 897 62

The effects of different dietary fats on peritoneal macrophage plasma membrane fluidity, intracellular cyclic AMP (cAMP) production, GTP hydrolysis and TNF binding and TNF-induced IL1 and IL6 production was investigated. After a four week period, fluidity, as determined by both fluorescence recovery after photobleaching (FRAP) and anisotropy was lowest and highest in animals fed corn and fish oil respectively. After eight weeks feeding, lateral membrane movements were decreased substantially in fish, olive and coconut oil fed dietary groups, whereas an increase in the corn oil fed group was observed, no effect was observed in macrophages from the butter fed group. However, an increase in the packing was observed in macrophages from all dietary groups except in the olive oil fed group. GTPase values for the coconut oil and butter groups were higher than in any other dietary group. After receiving the diet for 8 weeks these differences between the groups were no longer apparent. Exposure of macrophages to TNF had no effect on the rate of GTP hydrolysis. A major enhancement of cAMP production became apparent between weeks 4 and 8 of dietary treatment. After 4 weeks on the diet, values were significantly higher from cells of animals fed corn and olive oils than from animals fed fish oil. After 8 weeks, while there was a general enhancement of production, further differences became apparent. Feeding corn and coconut oils resulted in the highest values and olive oil and chow in the lowest. It is proposed that fats rich in n-3 fatty acids (fish oils) alter membrane fluidity, decrease TNF binding affinity, GTPase activity and cAMP production which appears not to modify cytokine production after short term dietary supplementation. However, after long term feeding it appears that increases in the sensitivity of the TNF receptors plays a major role in modifying cytokine production.
Mol Cell Biochem 1997 Jan
PMID:The influence of membrane fluidity, TNF receptor binding, cAMP production and GTPase activity on macrophage cytokine production in rats fed a variety of fat diets. 904 30


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