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PubMed1995

Pulmonary penetration of ceftazidime.

For an antibiotic to be effective in lower respiratory tract infections, it should be available in adequate concentrations in respiratory tissues and fluids. Cephalosporins usually achieve modest concentrations in the respiratory tract. In this study we have determined the pulmonary penetration of intramuscularly administered ceftazidime (a single dose of 1 g). Levels of ceftazidime in bronchial secretions (BS), bronchial mucosa (BM), epithelial lining fluid (ELF), and serum (S) were measured by microbiological assay in 25 patients suffering from acute exacerbation of chronic bronchitis who were divided into 5 groups of 5 subjects according to sampling time (1, 2, 4, 8 and 12 hours after the administration of the antibiotic). The peak S level was high (39.89 +/- 10.42 micrograms/ml at 1 hour) and mean S concentrations decreased slowly and were still detectable at 12 hours (1.07 +/- 0.45 microgram/ml). In all other samples, mean concentrations were in excess of the ceftazidime minimum inhibitory concentrations (MICs) for many relevant respiratory pathogens (Haemophilus influenzae 0.15 microgram/ml; Moraxella catarrhalis 0.06 micrograms/ml; Streptococcus pneumoniae 0.15 micrograms/ml; Klebsiella pneumoniae 0.4 microgram/ml). Concentrations in BM (7.05 +/- 2.38, 8.14 +/- 2.23, 6.40 +/- 1.63, 4.06 +/- 0.99 and 0.45 +/- 0.27 microgram/g) were higher than that in BS (6.87 +/- 1.96, 6.54 +/- 1.84, 3.52 +/- 1.23, 1.56 +/- 0.92 and 0.23 +/- 0.19 microgram/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2003

The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow.

In vivo distribution of myeloid transcription factors during granulopoiesis was investigated by Northern and Western blotting in 3 neutrophil precursor populations from human bone marrow: immature (myeloblasts [MBs] and promyelocytes [PMs]); intermediate mature (myelocytes [MCs] and metamyelocytes [MMs]); and mature neutrophil cells (band cells [BCs] and segmented neutrophil cells [SCs]). Nonneutrophil cells were removed with magnetic-bead-coupled antibodies against CD2, CD3, CD14, CD19, CD56, CD61, glycophorin-A, and CD49d (BCs/SCs) before RNA and protein extraction. Polymorphonuclear neutrophils (PMNs) from peripheral blood depleted with anti-CD49d antibodies were also included. Expression of acute myeloid leukemia 1b (AML-1b), c-myb, GATA-1, and CCAAT/enhancer binding protein gamma (C/EBP-gamma) was seen primarily in MBs/PMs, and little expression was found in more mature cells. The level of C/EBP-alpha was constant in the bone marrow-derived cells and decreased in PMNs. C/EBP-epsilon was found primarily in MCs/MMs and was almost absent in more mature cells. Expression of C/EBP-beta, C/EBP-delta, and C/EBP-zeta was observed from the MC/MM stage onward, with peak levels in the most mature cells. The amount of PU.1 increased throughout maturation whereas the level of Elf-1 reached a nadir in MCs/MMs The PU.1 coactivator c-jun and c-jun's dimerization partner c-fos were both detectable in MCs/MMs and increased in amount with maturity. CCAAT displacement protein (CDP) was found at comparable levels at all stages of differentiation. This demonstrates a highly individualized expression of the transcription factors, which can form the basis for the heterogeneous expression of granule proteins during granulopoiesis and cell cycle arrest in metamyelocytes.

Antigens, CD↗
PubMed2005

Immune sensitization of equine bronchus: glutathione, IL-1beta expression and tissue responsiveness.

BACKGROUND: Increasing clinical epidemiological and experimental evidence indicates that excess of production of reactive oxygen free radicals (ROS) induced by an oxidative stress is involved in the pathogenesis of a number of human airway disorders, as well as equine recurrent airway obstruction. Free-radicals modulate the activation of transcription factors, such as nuclear factor-(NF)-kappaB and activator protein (AP)-1, in several different cells. This activation leads to expression of many pro-inflammatory cytokines, including interleukin (IL)-1beta. We have hypothesized that equine airway sensitization might induce an oxidative stress and increase the ROS production, which in turn might enhance a production of IL-1beta and airway hyperresponsiveness. METHODS: We have examined the effect of passive sensitization on IL-1beta mRNA expression and electrical field stimulation (EFS)-induced contraction in equine isolated bronchi, and the potential interference of reduced-glutathione (GSH), an antioxidant, with these responses. Bronchi passively sensitized with serum from animals suffering from heaves and having high total level of IgE, and control tissues, either pretreated or not with GSH (100 microM), were used to quantify IL-1beta mRNA. Other tissues were used to study the effect of EFS (3-10-25 Hz). RESULTS: Mean IL-1beta mRNA expression was higher in passively sensitized than in control rings. GSH significantly (p < 0.05) reduced the IL-1beta mRNA expression only in passively sensitized bronchi. ELF induced a frequency-dependent contraction in both non-sensitized and passively sensitized tissues, with a significantly greater response always observed in sensitized tissues. GSH did not modify the EFS-induced contraction in non-sensitized bronchi, but significantly (p < 0.05) decreased it in passively sensitized tissues. CONCLUSION: Our data indicate that the passive sensitization of equine bronchi induces inflammation and hyperresponsiveness. These effects might be due to an oxidative stress because a pretreatment with GSH decreased the increased IL-1beta mRNA expression and responsiveness to EFS of passively sensitized bronchi.

Animals↗
PubMed2003

Pulmonary surfactant disaturated-phosphatidylcholine (DSPC) turnover and pool size in newborn infants with congenital diaphragmatic hernia (CDH).

In animal CDH models, surfactant deficiency contributes to the pathophysiology of the condition but information on human disease is very limited. The aim of our study was to investigate surfactant kinetics in CDH newborns. We studied surfactant disaturated-phosphatidylcholine (DSPC) half-life, turnover and apparent pool size by stable isotope methodology in CDH newborns with no ExtraCorporeal Membrane Oxygenation (ECMO) support (n = 13, birth weight (BW) 3.2 +/- 2.2 kg, gestational age (GA) 39 +/- 0.4 wks, postnatal age 43 +/- 11 h) and in 8 term infants with no lung disease (CONTROLS, BW 2.7 +/- 0 kg, GA 38 +/- 0.8 wks, postnatal age 96 +/- 26 h). We administered a trace dose of 13C-palmitic acid dipalmitoyl-phosphatidylcholine (DPPC) through the endotracheal (ET) tube and we measured DSPC kinetics by gas chromatography-mass spectrometry from DSPC13C-enrichment decay curves obtained from sequential tracheal aspirates. DSPC amount from tracheal aspirates (TA-DSPC) was measured by gas chromatography. In CDH infants DSPC half-life was shorter (24 +/- 4 and 53 +/- 11 h, p = 0.01), turnover faster (0.6 +/- 0.1 and 1.5 +/- 0.3 d-1 p = 0.01), apparent pool size smaller (34 +/- 6 and 57 +/- 7 mg/kg body weight, p = 0.02) and tracheal aspirates DSPC amount lower (2.4 +/- 0.4 and 4.6 +/- 0.5 mg/mL Epithelial Lining Fluid (ELF), p = 0.007) than in CONTROLS. In conclusion surfactant kinetics is grossly abnormal in mechanically ventilated CDH. Whether alterations of DSPC kinetics in CDH infants are caused by a primary surfactant deficiency or are secondary to oxygen therapy and ventilator support has still to be determined.

Animals↗
PubMed1999

Precise developmental regulation of Ets family transcription factors during specification and commitment to the T cell lineage.

Ets family transcription factors control the expression of a large number of genes in hematopoietic cells. Here we show strikingly precise differential expression of a subset of these genes marking critical, early stages of mouse lymphocyte cell-type specification. Initially, the Ets family member factor Erg was identified during an arrayed cDNA library screen for genes encoding transcription factors expressed specifically during T cell lineage commitment. Multiparameter fluorescence-activated cell sorting for over a dozen cell surface markers was used to isolate 18 distinct primary-cell populations representing discrete T cell and B cell developmental stages, pluripotent lymphoid precursors, immature NK-like cells and myeloid hematopoietic cells. These populations were monitored for mRNA expression of the Erg, Ets-1, Ets-2, Fli-1, Tel, Elf-1, GABPalpha, PU.1 and Spi-B genes. The earliest stages in T cell differentiation show particularly dynamic Ets family gene regulation, with sharp transitions in expression correlating with specification and commitment events. Ets, Spi-B and PU.1 are expressed in these stages but not by later T-lineage cells. Erg is induced during T-lineage specification and then silenced permanently, after commitment, at the beta-selection checkpoint. Spi-B is transiently upregulated during commitment and then silenced at the same stage as Erg. T-lineage commitment itself is marked by repression of PU.1, a factor that regulates B-cell and myeloid genes. These results show that the set of Ets factors mobilized during T-lineage specification and commitment is different from the set that maintains T cell gene expression during thymocyte repertoire selection and in all classes of mature T cells.

Animals↗
PubMed1999

[Novel transcription factor MEF is associated with the function of lung epithelial cells].

Lysozyme is an important component of innate immunity against common pathogens at mucosal surfaces. We previously cloned and characterized the bovine lysozyme 5A (lys5A) promoter with the purpose of determining cis- and trans-acting elements controlling airway epithelial cell-specific expression. We found that such expression is controlled by protein binding to an ETS consensus sequence located approximately at -46 to -40 bp from the transcription start site. The identity of the ETS-related protein responsible for gene transactivation was unknown. In this study, we screened six ETS-related proteins by transient transfection into epithelial cells and fibroblasts. Results showed that among these factors, the myeloid Elf-I-like factor (MEF) was the most potent. Gel shift analysis of epithelial cell nuclear extracts using a lys5A probe including the ETS-binding site (-50/-31) yielded a single band with retarded mobility. This band was super-shifted by an antibody directed against MEF. Supporting the possibility that MEF is responsible for functional transactivation of lysozyme in epithelial cells, we found that antisense MEF mRNA decreased lys5A promoter activity and that MEF overexpression in stably transfected cells increased lysozyme mRNA and protein expression. We conclude that MEF is required for epithelial cell transactivation of lysozyme.

Animals↗
PubMed2006

Fluid shear stress induces less calcium response in a single primary osteocyte than in a single osteoblast: implication of different focal adhesion formation.

UNLABELLED: The immediate calcium response to fluid shear stress was compared between osteocytes and osteoblasts on glass using real-time calcium imaging. The osteoblasts were responsive to fluid shear stress of up to 2.4 Pa, whereas the osteocytes were not. The difference in flow-induced calcium may be related to differences in focal adhesion formation. INTRODUCTION: To explore the immediate response to mechanical stress in a bone cell population, we examined flow-induced calcium transients. In addition, the involvement of focal adhesion-related calcium transients in response to fluid flow in the cells was studied. MATERIALS AND METHODS: Bone cells were isolated from 16-day-old embryonic chicken calvaria by serial treatment with EDTA and collagenase. Single cells on glass without intercellular connections were subjected to fluid flow, and intracellular calcium concentration was measured using imaging with fluo-3. The identification of cell populations in the same field was performed with a chick osteocyte-specific antibody, OB7.3, and an alkaline phosphatase substrate, ELF-97, for osteoblast identification afterward. Immunofluorescence staining of vinculin was performed to visualize focal adhesions. RESULTS: The percentage of cells responding to fluid shear stress at 1.2 Pa was 5.5% in osteocytes, 32.4% in osteoblasts, and 45.6% in OB7.3/ELF-97-negative cells. Furthermore, osteoblasts and OB7.3/ELF-97-negative cells were more responsive to 2.4 Pa than 1.2 Pa, whereas osteocytes were less responsive. The elevation of calcium transients over baseline did not show any significant differences in the populations. To elucidate the mechanism accounting for the fact that single osteocytes are less sensitive to fluid shear stress of up to 2.4 Pa than osteoblasts, we studied focal adhesion-related calcium transients. First, we compared focal adhesion formation between osteocytes and osteoblasts and found a larger number of focal adhesions in osteoblasts than in osteocytes. Next, when the cells were pretreated with GRGDS (0.5 mM) before flow treatment, a significant reduction of calcium transients in osteoblasts (18%) was observed, whereas calcium transients in osteocytes were not changed by GRGDS. Control peptide GRGES did not reduce the calcium transients in either cell type. Furthermore, we confirmed that osteoblasts in calvaria showed a marked formation of vinculin plaques in the periphery of the cells. However, osteocytes in calvaria showed faint vinculin plaques only at the base of the processes. CONCLUSIONS: On glass, single osteocytes are less sensitive to fluid shear stress up to 2.4 Pa than osteoblasts. The difference in calcium transients might be related to differences in focal adhesion formation. Shear stress of a higher magnitude or direct deformation may be responsible for the mechanical response of osteocytes in bone.

Animals↗
PubMed2004

Regional differences in emphysema scores and BAL glutathione levels in HIV-infected individuals.

STUDY OBJECTIVES: Evidence exists that HIV-seropositive individuals may be at increased risk for the development of precocious pulmonary emphysema. HIV infection is also associated with antioxidant deficiency in both the serum and lungs, and it is therefore possible that increased oxidant stress may contribute to parenchymal lung injury occurring in the setting of HIV. We sought to determine the regional distribution of emphysema and regional distribution of glutathione (GSH) concentrations among HIV-seropositive subjects with emphysema. DESIGN: Cross-sectional evaluation of a prospective, longitudinal study. SETTING: University teaching hospital. SUBJECTS/MEASUREMENTS: HIV-seropositive subjects without AIDS-related pulmonary complications participating in a descriptive study of lung biology in HIV-seropositive individuals. Emphysema scoring and evaluation of emphysema lobar distribution was performed among 40 subjects with emphysema. Eleven subjects underwent BAL of the right middle lobe (RML) and right upper lobe (RUL) with measurement of epithelial lining fluid (ELF) GSH in each lobe. RESULTS: We found that the mean emphysema scores were much higher in the upper lobes compared to the rest of the lung. Mean GSH levels were significantly greater in the RUL compared to the RML. The regional differences were present in both smokers and nonsmokers. CONCLUSIONS: We conclude that in the setting of HIV, emphysema is more prominent and lung GSH concentrations are higher in the upper lobes. We hypothesize that the increased GSH may represent a compensatory response to increased oxidant stress in the upper lobes.

Adult↗
PubMed2006

Growth of Escherichia coli under extremely low-frequency electromagnetic fields.

The influence of extremely low-frequency (ELF) electromagnetic fields on Escherichia coli cultures in submerse fermentation was studied. The fermentation processes were carried out recycling the culture medium externally through a stainless steel tube inserted in a magnetic field generator (solenoid). The exposure time and electromagnetic induction were varied in a range of 1 to 12 h and 0.010 to 0.10 T, respectively, according to a Box-Wilson Central Composite Designs of face centered with five central points. Growth of E. coli could be altered (stimulated or inhibited) under magnetic fieldinduced effects. E. coli cultures exposed at 0.1 T during 6.5 h exhibited changes in its viability compared to unexposed cells, which was 100 times higher than the control. The magnetic field generator associated with the cellular suspension recycle is a new way of magnetic treatment in fermentation processes and could be appropriate to industrial scale up.

Dose-Response Relationship, Radiation↗
PubMed2005

ECG changes in humans exposed to 50 Hz magnetic fields.

Possible health issues of ELF EMFs include cardiovascular effects since both electrocardiogram and heart-rate changes have been reported in the literature. A non-linear relationship between field strength and biological response has been reported in some studies. In this study, a total of 59 subjects, divided into three independent magnetic field strength groups, were compared. A calculated 12-hour time weighted average (TWA) value of the fields was used as an exposure metric for each of the three locations ("low": 0.067 muT, "medium": 1.18 muT and "high": 5.2 muT) and subsequently used to estimate workers' exposure at these sites. Electrocardiograms were recorded in the resting position. Five parameters were derived from the ECG: heart rate (HR), duration of P wave and QRS wave, and duration of PR and QT intervals. The QT intervals were normalized to a heart rate of 60 (QTc). The obtained data were analyzed first by means of multivariate analysis of covariance and then oneway univariate analyses of covariances (ANCOVA) using exposure duration as a covariate. Only the ANCOVA on the QTc interval was significant. Our results suggest that the relationship between field strength and response is non-linear: the adjusted mean QTc values are similar between the "low" and the "high" group, but significantly lower in the "medium" group. One possible interpretation of our results is that a specific exposure pattern might be responsible for the non-linear effects observed, so that generally, characterizing exposure to electric and magnetic fields using simple metrics such as TWA may be insufficient.

Adult↗
PubMed2002

[Chromosome abnormalities caused by computer video display monitors' radiation].

OBJECTIVE: Concerns were raised about the potential damaging effects of electromagnetic field (EMF) radiation emissions of ELF (extremely low frequency) and VLF (very low frequency) computer video display monitors (VDM), it was assessed the frequency of structural chromosome abnormalities and investigated the cell cycle kinetics in individuals occupationally exposed to VDM radiation. METHODS: Chromosome aberrations were investigated in 2,000 first cell cycle metaphases obtained after 48-hour cultures of peripheral blood lymphocytes drawn from 10 individuals occupationally exposed to VDM radiation (group E) and 10 controls (group C). Cell cycle kinetics was studied using the mitotic index (MI) and cellular proliferation index (CPI). RESULTS: Statistical analysis showed significantly higher frequencies of anomalous metaphases (E=5.9%; C=3.7%) and anomaly/cell (E=0.066+/-0.026; C= 0.040+/-0.026) in individuals exposed to VDM radiation. The most common cytogenetic alterations seen were chromatid breaks at frequencies of 0.034+/-0.016 in group E and 0.016+/-0.015 in group C. There was no significant difference between MI and CPI frequencies in both groups. CONCLUSIONS: The study findings suggest genotoxic effects of EMF emissions revealed by the higher frequency of chromatid breaks in individuals exposed to VDM radiation. However, there is a need of further studies on EMF genetic effects using other investigation methods.

Adult↗
PubMed2000

Calculated electric field induced in bundles of long cells in the human body when it is exposed to low-frequency electric fields.

A theoretical analysis is made of the electric field induced in the interior of long cylindrical cells arranged in bundles of parallel cells embedded in the saline fluid in the human body exposed to extremely low-frequency (ELF) and very low-frequency (VLF) electric fields parallel to the length of the cells. Such bundles characterize muscle. The analysis parallels in many respects the earlier study of isolated long cells (King and Wu, Phys. Rev. E 58, 2363-2369, 1998) but has important added complications. It leads to a similar result: The field inside the membrane of each long cell is the same as the field just outside the membrane in the saline fluid; i.e., the membrane provides no shielding. While one might expect the presence of the neighboring cells to provide a shielding effect for each cell, the results of this study show quantitatively that this is not the case. In fact, the electric field in the interior of each of a bundle of long cells is seen to increase very slightly (of the order of 0.4%) when the cells in the bundle are moved close enough to be practically in contact.

Cell Membrane↗
PubMed2005

Therapeutic targets of misguided T cells in systemic lupus erythematosus.

It is widely accepted that T cells with defective function play a central role in the pathogenesis of systemic lupus erythematosus (SLE). The detailed molecular mechanism underlying the aberrant function of SLE T cells is now being revealed. The TCR zeta chain, transcription factor, elf-1, inflammation signal transducer NF-kB, and PKC theta have been identified as the responsible molecules. In contrast to the defective signal transduction molecules, surface structures such as adhesion molecules, and co-stimulators have been reported to increase in their expression and function. Glucocorticoids and immunosuppressive agents have greatly improved the outcome of acute diseases and 5-year survival rate. However, it is suggested that long-term survival and quality of life appears to be unsatisfactory. Although the medical management of SLE is not sufficient to warrant long-term survival of young patients, recent progress in anti-cytokine biologics therapy against rheumatoid arthritis (RA) has facilitated searching for the molecular targets of SLE. In this report, we briefly review the molecular basis of SLE pathogenesis, and discuss possible therapeutic targets in this disease, focusing particularly on signal transduction and adhesion molecules in T cells.

Animals↗
PubMed1996

Treatment of advanced gastric cancer with a modified regimen of etoposide/leucovorin/5-fluorouracil.

The efficacy and toxicity of a combination of etoposide 100 mg/m2/day iv on day 2-4, leucovorin 300 mg/m2/day iv, and 5-FU 500 mg/m2 day iv on day 1-5 every 4 weeks were assessed in 21 patients with advanced gastric cancer with measurable or evaluable diseases. Eight patients had an objective response, including 3 in CR. The overall response rate was 38.1% (95% CI 33.4-42.8%). Five of 8 patients who exhibited locally advanced and unresectable diseases had an objective response (2 CR, 3 PR). The response rate in patients with metastatic disease was 23.0% (95% CI 14.4-31.6%). The median progression-free interval and overall survival time were 7 and 10 months, respectively. The most frequent side effect was alopecia (Gr I/II 71.4%). No treatment-related death occurred. Modified ELF is a relatively effective and tolerable combination regimen for advanced gastric cancer and can be safely administered to elderly patients and patients with systemic diseases.

Adenocarcinoma↗
PubMed1996

Differential depletion of human respiratory tract antioxidants in response to ozone challenge.

The toxicity of ozone, the major component of photochemical smog, is related to its powerful oxidising ability, and many of its deleterious effects are mediated through free radical reactions. As the majority of ozone oxidation events are thought to be confined to the pulmonary epithelial lining fluid, we studied the interaction of ozone with a range of small molecular weight antioxidants found within this compartment: ascorbic acid (AH2), uric acid (UA), and reduced glutathione (GSH). Epithelial lining fluid obtained as bronchoalveolar lavage (BAL) fluid, was taken from 16 male subjects and the antioxidant concentrations determined for each subject. BAL fluid samples from nine of these subjects were then exposed, using an interfacial exposure system, to a range (50-1000 ppb) of ozone concentrations. Both AH2 and UA were consumed by ozone in a time and ozone concentration dependent manner, with mean consumption rates of 1.7 +/- 0.8 and 1.0 +/- 0.5 pmol L-1 s-1 ppb-1, respectively. Considerable intersubject variation was however observed. The individual rates of consumption for each antioxidant were significantly correlated with the respective initial antioxidant concentration. In contrast, although GSH was consumed at 50 ppb ozone, the rate of consumption did not change with increasing ozone concentration. We conclude that there is differential depletion of BAL fluid antioxidants, suggesting a reactivity hierarchy toward ozone in human ELF of AH2 > UA > > GSH.

Antioxidants↗
PubMed2003

How much are anesthesiologists exposed to electromagnetic fields in operating rooms?

Numerous electronic devices have been introduced into the operating room. Although little is known about the relationship between exposure to electromagnetic fields (EMF) and health hazards, some authors reported its association with cancer or other diseases. We measured the amount of EMF exposure that an anesthesiologist gets in the operating room. The density of the magnetic field was checked by an extremely low frequency (ELF) field strength measurement system in the 19 operating rooms of our hospital. We measured the magnetic field intensity at a distance of 30 cm, 50 cm, and at the place where the anesthesiologist usually stands from the center of the main monitor. The average exposure quantities of magnetic fields in 19 operating rooms were 2.22 +/- 1.13 mG at 30 cm, 1.29 +/- 0.84 mG at 50 cm and 1.00 +/- 0.78 mG at the anesthesiologist's standing points respectively. Because quantities over 2 or 3 mG were accepted to be high radiation levels of EMF by many reports describing the hazards of EMF, we set 2 mG to be the cutoff value. In some of the 19 operating rooms, the measured EMF density exceeded our cutoff value. Although the health hazards related to EMF exposure are still equivocal, anesthesiologists should consider making an effort to improve their environment and reduce their exposure to EMF.

Anesthesiology↗
PubMed2001

Function and factor interactions of a locus control region element in the mouse T cell receptor-alpha/Dad1 gene locus.

Locus control regions (LCRs) refer to cis-acting elements composed of several DNase I hypersensitive sites, which synergize to protect transgenes from integration-site dependent effects in a tissue-specific manner. LCRs have been identified in many immunologically important gene loci, including one between the TCRdelta/TCRalpha gene segments and the ubiquitously expressed Dad1 gene. Expression of a transgene under the control of all the LCR elements is T cell specific. However, a subfragment of this LCR is functional in a wide variety of tissues. How a ubiquitously active element can participate in tissue-restricted LCR activity is not clear. In this study, we localize the ubiquitously active sequences of the TCR-alpha LCR to an 800-bp region containing a prominent DNase hypersensitive site. In isolation, the activity in this region suppresses position effect transgene silencing in many tissues. A combination of in vivo footprint examination of this element in widely active transgene and EMSAs revealed tissue-unrestricted factor occupancy patterns and binding of several ubiquitously expressed transcription factors. In contrast, tissue-specific, differential protein occupancies at this element were observed in the endogenous locus or full-length LCR transgene. We identified tissue-restricted AML-1 and Elf-1 as proteins that potentially act via this element. These data demonstrate that a widely active LCR module can synergize with other LCR components to produce tissue-specific LCR activity through differential protein occupancy and function and provide evidence to support a role for this LCR module in the regulation of both TCR and Dad1 genes.

Animals↗
PubMed2003

Regulation of the human Fc epsilon RI alpha-chain distal promoter.

The alpha-chain of the high affinity receptor for IgE (Fc epsilon RI) is essential for cell surface expression of Fc epsilon RI and binding of the IgE Ab. The human alpha-chain gene possesses two promoters: the proximal promoter, which is highly conserved with that of rodent; and the distal promoter, the structure and role of which are largely unknown. Transcriptional regulation of the alpha-chain distal promoter was investigated in this study. Transient reporter assay revealed critical region for transcription activity located within -27/-17. EMSA identified Elf-1, YY1, and PU.1 as transcription factors binding to this region. In contrast to the proximal promoter, which was trans-activated by YY1 and PU.1, these transcription factors exhibited repressive function on this promoter. Addition of IL-4 caused a marked increase in transcription from the distal promoter and subsequently increased the intracellular production of the alpha-chain. These results indicate that IL-4-dependent up-regulation of the human alpha-chain was due to enhancement of distal promoter activity and suggests that the two promoters have different regulatory mechanisms for alpha-chain expression.

Base Sequence↗