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Macrophage development is regulated by a complex set of hormone-like molecules and cell adhesion events that control the growth and differentiation of progenitor cells. The macrophage scavenger receptor (SR) gene becomes markedly upregulated during the final stages of monocyte-to-macrophage differentiation and provides a model for the identification and characterization of transcription factors that control this process. In this report, we have identified three genomic regulatory elements that are required for transactivation of the SR gene in the THP-1 monocytic leukemia cell line following induction of macrophage differentiation by tetradecanoyl phorbol acetate. Each of these regulatory elements contains a near-consensus binding site for members of the AP-1 gene family, while the two most quantitatively important elements also contain juxtaposed binding sites for ets domain transcription factors. We demonstrate that tetradecanoyl phorbol acetate treatment results in a marked and prolonged increase in AP-1 binding activity on these elements, which can be accounted for almost entirely by c-jun and junB. These proteins in turn form ternary complexes with additional factors that bind to the adjacent ets recognition motifs. Several indirect lines of evidence indicate that ets2 represents a component of this ternary complex. The combined expression of c-jun, ets2, and a constitutive form of ras result in synergistic increases in transcription from promoters containing the SR regulatory elements. These observations suggest that SR gene expression is regulated via a signal transduction pathway involving ras, AP-1, and ets domain proteins and imply that at least some of the signalling components involved in ras-dependent growth are also utilized to promote the expression of genes involved in terminal differentiation.
Mol Cell Biol 1994 Mar
PMID:Combinatorial interactions between AP-1 and ets domain proteins contribute to the developmental regulation of the macrophage scavenger receptor gene. 811 43

Latent cytomegalovirus (CMV) infection is often reactivated in the lung. We postulated that this reactivation could occur by stimulation of the CMV major immediate early (IE) promoter by other viruses that infect the lung. The specific aim of this study was to investigate whether adenovirus early proteins could stimulate the CMV IE promoter in inflammatory cells. We transfected the monocyte/macrophage THP-1 cell line and the T-lymphocyte Jurkat cell line with plasmids coding for adenovirus E1A 12S or 13S proteins, along with a plasmid containing the CMV IE promoter region linked to the chloramphenicol acetyltransferase (CAT) reporter gene. In unstimulated THP-1 cells, the E1A 13S gene product increased CMV IE CAT activity by 18-fold compared with cells containing the control E1A plasmid. This effect was not seen in cells transfected with the E1A 12S plasmid. There was a similar effect of the E1A 13S gene product in LPS-stimulated THP-1 cells. In unstimulated Jurkat cells, the E1A 13S gene product stimulated CMV IE CAT activity by 19-fold compared with cells containing the E1A control plasmid; the E1A 12S gene product had no effect. There was a similar effect of the 13S E1A gene product in phorbol myristate acetate-stimulated Jurkat cells. These findings demonstrate that the CMV IE promoter can be stimulated by early viral proteins of adenovirus in inflammatory cells. These observations could be important for understanding the reactivation of latent CMV infection.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Adenovirus E1A 13S gene product up-regulates the cytomegalovirus major immediate early promoter. 813 60

Manifestations of HIV-1 infection such as fever, hypergammaglobulinemia, and interstitial pneumonitis may be due to increased production of inflammatory cytokines such as interleukin-1 and interleukin-6 (IL-6). Monocytes/macrophages of HIV-1-infected individuals have been noted to produce increased amounts of IL-6, as well as to have enhanced accessory cell function. These studies examined the ability of HIV-1 tat, an important HIV-1 regulatory gene, to modulate monocyte/macrophage function. In these experiments, HIV-1 tat-transfected THP-1 cells, a monocytic cell line, enhanced THP-1 immune accessory cell function in the presence of pokeweed mitogen and concanavalin A. HIV-1 tat-transfected cells also increased production of lipopolysaccharide-stimulated IL-6 mRNA and IL-6 protein. The ability of monocytes/macrophages to support HIV-1 production while exhibiting little or no cytopathic effects allows these cells to serve as a reservoir for the virus. The ability of HIV-1 tat to regulate cellular function in monocytes/macrophages may play an important part in the pathogenesis of HIV-1 infection.
Am J Respir Cell Mol Biol 1994 May
PMID:Modulation of accessory cell function and interleukin-6 production by the HIV-1 tat gene. 817 23

The human monocytic leukemia cell line THP-1 differentiates into macrophage-like cells when treated with a variety of agents, including 12-O-tetradecanoylphorbol-13-acetate (TPA). We show here that during this process, the expression of heme oxygenase, a rate-limiting enzyme in heme catabolism, is induced. Treatment with TPA increases heme oxygenase mRNA in other myelomonocytic cell lines also, but not in cell lines of other lineages, such as HeLa cells. Increased heme oxygenase activity may represent one of the functions of activated macrophages, which sequestrate senescent erythrocytes and degrade heme derived from hemoglobin. This cell-type-specific induction by TPA treatment further investigated with respect to transcriptional regulation. We defined a cis-regulatory element, 5'-GTCATATGAC-3', located in the 5'-flanking region (positions -156 to -147) of the human heme oxygenase gene, which confers inducibility by TPA in THP-1 cells but not in HeLa cells. Nuclear proteins that bind to this element, which may be responsible for the cell specificity, were identified in THP-1 nuclear extracts. This element contains the consensus motif CANNTG, to which a large family of basic helix-loop-helix proteins binds. Our results suggest a novel mechanism of TPA-mediated transcriptional regulation in myelomonocytic cell lines.
Mol Cell Biol 1993 Dec
PMID:Identification of a cis-regulatory element and putative trans-acting factors responsible for 12-O-tetradecanoylphorbol-13-acetate (TPA)-mediated induction of heme oxygenase expression in myelomonocytic cell lines. 824 3

Transfection of U937 and THP-1 cells with a recombinant plasmid, pIL1(4.0kb)-CAT, containing 4 kb of the interleukin 1 beta (IL-1 beta) gene upstream regulatory sequence resulted in inducer-dependent expression of chloramphenicol acetyltransferase activity. Treatment of the transfected cells with various combinations of the inducers lipopolysaccharide, phorbol myristate acetate, and dibutyryl cyclic AMP upregulated the IL-1 beta promoter. In U937 and THP-1 cells, maximum stimulation of both the endogenous IL-1 beta gene and pIL1(4.0kb)-CAT transfectants was observed following treatment with the combination of inducing agents lipopolysaccharide-phorbol myristate acetate-dibutyryl cyclic AMP. This combination of inducing agents was used to identify and study, at the molecular level, some of the regulatory elements necessary for induction of the IL-1 beta gene. A series of 5' deletion derivatives of the upstream regulatory sequence were used in transient transfection assays to identify an 80-bp fragment located between -2720 and -2800 bp upstream of the mRNA start site that was required for induction. Exonuclease III mapping, electrophoretic mobility shift assays (EMSA), and DNA sequence analysis of this region were used to identify a transcription factor binding sequence which contained a potential cyclic AMP response element (CRE/ATF)- and NF-kappa B-like binding site. Site-directed mutagenesis of the CRE/ATF-like site resulted in the loss of binding of a specific factor or factors as determined by EMSA. The loss of binding activity directly correlated with a loss of approximately 75% of promoter activity as determined in transient transfection assays. As determined by EMSA, the factor binding to the CRE/ATF-like site was present in nuclear extracts prepared from both uninduced and induced THP-1 and U937 cells. However, the intensity of the band appeared to be increased when nuclear extracts from induced cells were used. In contrast to the CRE/ATF mutation, which resulted in the loss of promoter activity, mutation of the NF-kappa B-like site resulted in a moderate increase in activity in U937 cells. A similar increase in promoter activity was not observed in THP-1 cells. From these studies, we conclude that a CRE/ATF-like site and a factor or factors interacting with this site are essential for the maximum induction of the IL-1 beta gene in stimulated U937 and THP-1 cells.
Mol Cell Biol 1993 Nov
PMID:A CRE/ATF-like site in the upstream regulatory sequence of the human interleukin 1 beta gene is necessary for induction in U937 and THP-1 monocytic cell lines. 841 64

The human high-affinity receptor for the constant region of immunoglobulin G (human Fc gamma R1) is encoded by two mRNAs induced selectively by gamma interferon (IFN-gamma) and expressed in cells of myeloid lineage. The cis-DNA element (GRR) previously found to confer IFN-gamma responsiveness to this gene acts as an inducible enhancer and is the target of an IFN-gamma-activated factor(s) (GIRE-BP) in cells of different origins. Although the GRR motif is not related to the DNA elements involved in the regulation of other IFN-stimulated genes, GIRE-BP binding depends on the IFN-gamma-dependent activation of the 91-kDa protein known to be one of the factors of a transcriptional complex activated by IFN-alpha. Deletions of the Fc gamma R1 promoter allowed us to identify a 25-bp element, downstream from the GRR motif, conferring cell-type-specific expression. This element, called MATE (myeloid activating transcription element), is the DNA target for constitutive factors forming two complexes, MATE-BP1 and MATE-BP2. In accordance with the functional analysis, MATE-BP binding activities were detected in extracts prepared from myeloid cell lines such as THP-1, HL-60, and U-937 but not in HeLa cell extracts. The MATE motif is present not only in the promoter of other Fc receptor genes but also in several promoters of genes whose expression is restricted to monocytic cells. Our results suggest that human Fc gamma R1 gene expression in myeloid cells is initiated by the interaction of IFN-gamma-activated factors with cell-type-specific factors through their binding to the GRR and MATE motifs.
Mol Cell Biol 1993 Apr
PMID:Two cis-DNA elements involved in myeloid-cell-specific expression and gamma interferon (IFN-gamma) activation of the human high-affinity Fc gamma receptor gene: a novel IFN regulatory mechanism. 845 6

The effects of sodium phenobarbital and sodium barbital on the activity of the particulate and cytosolic 5 alpha-dihydroprogesterone 3 alpha-hydroxysteroid oxidoreductases (3 alpha-HSORs) of female rat anterior pituitary were investigated. By altering the 3 alpha-HSOR catalyzed conversion of 5 alpha-dihydroprogesterone (5 alpha-DHP) to 3 alpha,5 alpha-tetrahydroprogesterone (3 alpha,5 alpha-THP), these barbiturates could influence the in situ production of 3 alpha,5 alpha-THP. 3 alpha,5 alpha-THP has potent barbiturate-like effects on brain GABAA receptors. Both phenobarbital and 3 alpha,5 alpha-THP can affect gonadotropin release in female rats. In vitro incubations of each 3 alpha-HSOR activity were assayed in the presence of sodium phenobarbital (0.1 to 10.0 mM) or sodium barbital (1.0 to 10.0 mM). Since both 3 alpha-HSOR activities catalyze the reversible oxidoreduction of 5 alpha-DHP and 3 alpha,5 alpha-THP, we examined the effect of these barbiturates not only on the conversion of 5 alpha-DHP to 3 alpha,5 alpha-THP (reductive reaction) but also on the "back conversion" of 3 alpha,5 alpha-THP to 5 alpha-DHP (oxidative reaction). The results indicate that both phenobarbital and, to a lesser extent barbital, significantly affected the activities of the two 3 alpha-HSORs in both reductive and oxidative directions. In the reductive direction, phenobarbital inhibited the activity (33%) of both cytosolic and particulate enzymes which would presumably decrease the levels of 3 alpha,5 alpha-THP. In the oxidative direction, a pattern of stimulation was observed (20 to 100%). Thus, this stimulatory effect on the oxidative conversion of 3 alpha,5 alpha-THP to 5 alpha-DHP, which would presumably also decrease 3 alpha,5 alpha-THP levels, appears correlated with the inhibitory effect of these barbiturates on the reductive conversion of 5 alpha-DHP to 3 alpha,5 alpha-THP. Sodium barbital exhibited somewhat similar effects. These changes suggest that barbiturates can lower 3 alpha,5 alpha-THP levels in the anterior pituitary. The results also suggest the possibility that lowered 3 alpha,5 alpha-THP levels may be involved, at least in part, in the reduction of gonadotropin release by barbiturates.
J Steroid Biochem Mol Biol 1993 Apr
PMID:Barbiturates modulate the activity of the pituitary 3 alpha-hydroxysteroid oxidoreductases and inhibit their production of 3 alpha,5 alpha-tetrahydroprogesterone. 849 36

Members of the myc oncogene family such as c, N-, and L-myc are expressed in many malignant tumors. Expression of c-, N-, and L-myc oncogenes in 7 human neuroblastoma cell lines (GOTO, IMR-32, TGW, SCCH-26, TNB 9, NBL-S, and SK-N-SH), a human small cell lung carcinoma SBC-5 cell line, and a human monocytic leukemia THP-1-S cell line at mRNA and protein levels was studied to know the specificity of a newly developed antibody against homologous region at C-terminus of N-Myc, designated as anti pan-Myc antibody. By RT-PCR and immunoblot analysis, coexpression of three myc genes was detected in all neuroblastoma cell lines tested. c-and L-myc expression were observed that anti pan-Myc antibody recognizes c-Myc and N-Myc proteins but not L-Myc. These results indicate that neuroblastoma cells may acquire an aberrant transcriptional control system in myc family gene expression.
Biochem Mol Biol Int 1995 Aug
PMID:Coexpression of the myc gene family members in human neuroblastoma cell lines. 853 84

Certain osteoclastic markers (multinucleation and tartrate-resistant acid phosphatase) were induced in human leukemia HL-60 cells by treatment with 10(-7) M 1,25-dihydroxy-vitamin D3 [1,25(OH)2D3] for 10 days. However, no formation of pits on a bone substrate by vitamin-treated HL-60 cells was detected. Expression of calcitonin receptors (CTR), another osteoclastic marker, was examined by means of the reverse transcriptase polymerase chain reaction. The human CTR-cDNA (T47D isotype) was amplified from untreated HL-60 cells, but not from cells treated with 1,25(OH)2D3. The CTR mRNA disappeared within 24 h after the treatment. Thus, 1,25(OH)2D3-differentiated HL-60 cells failed to show two intrinsic characteristics of osteoclasts, pit formation on a bone substrate and expression of CTR. We then examined the expression of CTR on established human leukemia cell lines. The CTR mRNA was expressed in myeloblastic ML-1 and promyelocytic HL-60 leukemia cells but not in more mature macrophage-like cell lines, U-937 and THP-1 cells. Neither B cell leukemia BALL-1, T cell leukemia Jurkat, promegakaryoblastic leukemia Meg-J, nor cervix uteri carcinoma HeLa S3 cells amplified the CTR products. The cDNA of BIN67-isotype CTR, that has an additional 16-amino acid insert in the putative first intracellular loop of T47D-type CTR [Kuestner et al. (1994) Mol. Pharmacol. 46, 246-255], was amplified by neither strain tested. It was suggested that the T47D-type CTR is a novel differentiation antigen of immature myeloid lineage cells.
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PMID:Expression of calcitonin receptors on human myeloid leukemia cells. 854 84

The pregnancy-specific glycoproteins (PSG) form a large family of essential pregnancy proteins, but their biological function is unknown. We have investigated whether one function of the PSG is to interact with cells of the maternal immune system. Normal human peripheral blood mononuclear cells, activated with phorbol ester, are shown to bind to purified placental PSG. This binding activity can be mimicked using a chemically synthesized peptide ligand containing the Arg-Gly-Asp (RGD) motif present in the N-terminal domain of PSG11s. The PSG11s receptors are present on cells of the myeloid cell lineage but not of the T cell or B cell lineages. The binding is mediated in part by the RGD motif and can be competed against by appropriate RGD-containing, but not Arg-Ala-Asp (RAD)-containing, ligands. Ligand binding requires a functional cytoskeleton. By examining the U937 and THP-1 promonocyte cell lines, the presence of receptors with two different binding characteristics are demonstrated. The THP-1 receptor is identified by chemical cross-linking as a protein of 46 kilodaltons (kDa), and affinity chromatography demonstrates the presence of three protein species of 32 kDa, 16.8 kDa, and 15.9 kDa, suggesting the receptor has multiple subunits.
Mol Endocrinol 1995 Oct
PMID:A motif in PSG11s mediates binding to a receptor on the surface of the promonocyte cell line THP-1. 854 38


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