RESUMEN
A pivotal role has been assigned to Myb in the control of myeloid cell growth. Although Myb is a target of retinoic acid, little is known about the mechanisms by which it may contribute to induced growth arrest in leukemia cells. Indeed, few Myb target genes are known to be linked to proliferation. Myeloblastin is involved in the control of proliferation in myeloid leukemia cells. It is expressed early during hematopoiesis and is a granulocyte colony-stimulating factor-responsive gene. Myeloblastin can confer factor-independent growth to hematopoietic cells, an early step in leukemia transformation. The myeloblastin promoter contains PU.1, C/EBP, and Myb binding sites, each of which are critical for constitutive expression in myeloid cells. Inhibition of myeloblastin expression in leukemia cells growth-arrested by retinoic acid is demonstrated to depend on Myb down-regulation. Myb is shown to induce myeloblastin expression and abolish its down-regulation by retinoic acid. Altogether, the data offer a clue as to how a myeloid-specific transcriptional machinery can be accessible to regulation by retinoic acid and point to myeloblastin as a novel target of Myb. This link between Myb and myeloblastin suggests a previously nonidentified Myb pathway through which growth arrest is induced by retinoic acid in myeloid leukemia cells.
Asunto(s)
Antineoplásicos/farmacología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Proteínas de Neoplasias/genética , Proteínas Proto-Oncogénicas c-myb/fisiología , Serina Endopeptidasas/genética , Factores de Transcripción , Transcripción Genética , Tretinoina/farmacología , Animales , Secuencia de Bases , Sitios de Unión , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Proteína beta Potenciadora de Unión a CCAAT/metabolismo , Proteína delta de Unión al Potenciador CCAAT , Proteínas Potenciadoras de Unión a CCAAT/metabolismo , Células COS , División Celular/efectos de los fármacos , Chlorocebus aethiops , Genes myb , Datos de Secuencia Molecular , Mieloblastina , Proteínas de Neoplasias/biosíntesis , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-myb/biosíntesis , Proteínas Recombinantes de Fusión/metabolismo , Eliminación de Secuencia , Transactivadores/metabolismo , TransfecciónRESUMEN
Proteinase 3 (PR3), a serine proteinase which can degrade lung tissue, is present in the cystic fibrosis (CF) sputum. In the present study, PR3 protein and mRNA expression was determined in circulating neutrophils and monocytes. CF neutrophils contained similar PR3 concentrations as healthy controls and poorly expressed PR3 mRNA. In contrast, CF monocytes showed significantly higher PR3 concentrations than controls, together with an upregulation of PR3 mRNA expression especially during pulmonary exacerbation. Interestingly, antibiotic treatment fully abrogated PR3 mRNA expression and decreased PR3 protein in monocytes. Our findings highlight a potential role of monocyte-derived PR3 in CF-associated airway inflammation.
Asunto(s)
Infecciones Bacterianas/enzimología , Fibrosis Quística/enzimología , Monocitos/enzimología , Neutrófilos/enzimología , ARN Mensajero/análisis , Serina Endopeptidasas/genética , Adolescente , Adulto , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Infecciones Bacterianas/complicaciones , Infecciones Bacterianas/tratamiento farmacológico , Niño , Preescolar , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Femenino , Humanos , Lactante , Masculino , Mieloblastina , Peroxidasa/genética , ARN Mensajero/efectos de los fármacos , Valores de Referencia , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/metabolismo , Esputo/química , Regulación hacia ArribaRESUMEN
Increase of the prevalence of allergy these last 20 years is in part secondary to the modification of the allergenic charge of our environment. The specific immunotherapy (SIT) is the only etiologic treatment of the allergic disease and numbers of authors believe that, for the future, this treatment could change the natural history of the respiratory allergy, provided that it is realised early in the first years of life. Several experimental studies show that the process of the SIT could be the restoration of the Th1 cell/Th2 cell balance which is reversed in allergies. However, indications of SIT have to be carefully selected. The ideal indication is the single sensitized asthma, and treatment has to be started in the first years of life, at the onset of the asthmatic disease, before a definitive remodelling of the respiratory airways induced by inflammation. Subcutaneous SIT is for the moment the only effective route confirmed by several controlled trials, in particular for grass pollens, possibly for house dust, pet danders and mite allergens. Risk of syndromic effects, present all the time of the SIT protocol, can be prevented by rigorous use of the SIT according to the European consensus. The advent of recombinant allergens, in particular by complementary DNA (cDNA) modified by site-directed mutagenesis, could tip the immune response to a Th-1 like response instead of a Th-2 like response (IgE mediated) and result in a better tolerated and more efficacy immunomodulation.
Asunto(s)
Desensibilización Inmunológica , Hipersensibilidad Respiratoria/terapia , Factores de Edad , Alérgenos/administración & dosificación , Alérgenos/inmunología , Asma/inmunología , Asma/terapia , Niño , Preescolar , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Humanos , Inmunoglobulina E/inmunología , Lactante , Oportunidad Relativa , Hipersensibilidad Respiratoria/inmunología , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
Proteinase 3 (PR3), is a matrix-degrading serine proteinase expressed in different hematopoietic cell lineages. The PR3 protein appears to regulate the myeloid differentiation and was found to be the autoantigen associated with Wegener granulomatosis. We have isolated and characterized the gene for mouse PR3 (mPR3) and determined its chromosomal location. The gene has been localized to Chromosome (Chr) 10. Comparison of mouse PR3 genomic structure with that of its human counterpart indicates that: 1) the mPR3 gene spans 7 kb organized in 5 exons and 4 introns, 2) the codons of His-Asp-Ser of the catalytic site are conserved and spread out over different exons, similar to the human gene, and 3) the gene product encodes a pre-proform of the protein. Knowledge of the structure and chromosomal location of the mPR3 gene may help better the understanding of the temporal and cell-specific expression of mouse PR3.
Asunto(s)
Mapeo Cromosómico , Exones , Intrones , Serina Endopeptidasas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , ADN , Ligamiento Genético , Granulomatosis con Poliangitis/genética , Humanos , Ratones , MieloblastinaRESUMEN
UNLABELLED: The aim of this study was to document plasma retinol status and nocturnal vision in ten eutrophic adolescents with cystic fibrosis (CF) receiving daily retinol supplementation. Plasma retinol, alpha and beta carotenes and retinol binding protein were measured in ten clinically stable CF patients (mean age: 14.3 years; Shwachman score: 80-100). Nocturnal vision evaluation was performed with a Beyne optometer. Plasma retinol (mean 0.42 +/- 0.16 mg/l), alpha carotene and beta carotene levels were below the lower limit of normal in all but one patient. Five out of ten patients with normal standard opthalmological examination presented a poor (n = 3 patients) or a pathological (n = 2) dark adaptation test. These two patients showed a dramatic increase in nocturnal vision after 1 year of adapted retinol supplementation. CONCLUSION: Low vitamin A levels occur frequently in clinically stable, eutrophic and retinol supplemented CF adolescents. Since vitamin A deficiency is associated with poor nocturnal vision and since this pattern can be reversed by adapted retinol supplementation, we recommend monitoring plasma vitamin A levels in CF patients and evaluation of dark adaptation in retinol deficient patients.