receptor mRNA in Human Bronchial Epithelium

Despite the central role bronchial epithelial cells play in asthmatic reactions, and the widespread use of inhaled corticosteroids in asthma, no information is available on the effect of glucocorticoids on glucocorticoid- receptor (GR) gene expression. In this study, the effect of budesonide on a- and ~-GR gene expression in human bronchial epithelial cells was investigated in vitro and in vivo. A bronchial epithelial cell line was exposed in vitro to budesonide, and a dose- and time-dependent synchronous downregulation of a- and ~-GR mRNA was observed. A l-h exposure resulted in a reversible and re­ duced downregulation as compared with continuous exposure. In healthy volunteers (n = 10), no differ­ ence on average was present in GR mRNAexpression before or after 4 wk of budesonide inhalation in either bronchial epithelial cells or alveolar macrophages. The time between the last inhalation and sampling of cells ranged from 0.5 to 8 h. However, a significant downregulation of a-GR mRNAwas observed when the time between the last inhalation and sampling of cells was more than 2 h. Normali­ zation of the downregulation of GR mRNAexpression in bronchial epithelial cells is explained by the pharmacokinetics of inhaled budesonide in the human lung. Kom SH, Wouten EFM, Wessellng G, Arends J-W, Thunnissen FBJM. In vitro and in vivo modulation ofa- and l3-glucocortlcold-receptor mRNA in human bronchial epithelium. AM J RESPIR CRIT CARE MED 1997;155:1117-1122.

[1]  I. Adcock,et al.  Glucocorticoid receptor localization in normal and asthmatic lung. , 1996, American journal of respiratory and critical care medicine.

[2]  F. Bach,et al.  Glucocorticoid-mediated Repression of NFκB Activity in Endothelial Cells Does Not Involve Induction of IκBα Synthesis* , 1996, The Journal of Biological Chemistry.

[3]  S. Erzurum,et al.  Continuous nitric oxide synthesis by inducible nitric oxide synthase in normal human airway epithelium in vivo. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[4]  I. Adcock,et al.  Beta-adrenoceptor agonists interfere with glucocorticoid receptor DNA binding in rat lung. , 1995, European journal of pharmacology.

[5]  P. Barnes,et al.  Inhaled glucocorticoids for asthma. , 1995, The New England journal of medicine.

[6]  I. Adcock,et al.  Effects of glucocorticoids on transcription factor activation in human peripheral blood mononuclear cells. , 1995, The American journal of physiology.

[7]  W. Vedeckis,et al.  Coordinate regulation of glucocorticoid receptor and c-jun mRNA levels: evidence for cross-talk between two signaling pathways' at the transcriptional level. , 1994, Molecular endocrinology.

[8]  K. Yamamoto,et al.  Analysis of the DNA-binding affinity, sequence specificity and context dependence of the glucocorticoid receptor zinc finger region. , 1994, Journal of molecular biology.

[9]  I. Pavord,et al.  Pharmacokinetic Optimisation of Inhaled Steroid Therapy in Asthma , 1993, Clinical pharmacokinetics.

[10]  O Selroos,et al.  Relationship between lung tissue and blood plasma concentrations of inhaled budesonide. , 1993, Biopharmaceutics & drug disposition.

[11]  K. Yamamoto,et al.  Glucocorticoid receptor-cAMP response element-binding protein interaction and the response of the phosphoenolpyruvate carboxykinase gene to glucocorticoids. , 1993, The Journal of biological chemistry.

[12]  J. Gustafsson,et al.  Glucocorticoid receptor mRNA expression in pulmonary alveolar macrophages in sarcoidosis. , 1991, Chest.

[13]  S. Detera-Wadleigh,et al.  The genomic structure of the human glucocorticoid receptor. , 1991, The Journal of biological chemistry.

[14]  S. Freier,et al.  Modulation of glucocorticoid receptor expression , 1991 .

[15]  Stephan Gebel,et al.  Antitumor promotion and antiinflammation: Down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone , 1990, Cell.

[16]  M. Beato.  Gene regulation by steroid hormones , 1989, Cell.

[17]  J. Murray.  The history of corticosteroids. , 1989, Acta dermato-venereologica. Supplementum.

[18]  L. Poellinger,et al.  Regulation of glucocorticoid receptor expression: evidence for transcriptional and posttranslational mechanisms. , 1988, Molecular endocrinology.

[19]  C. Harris,et al.  Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate coprecipitation with a plasmid containing SV40 early region genes. , 1988, Cancer research.

[20]  S. Rosewicz,et al.  Mechanism of glucocorticoid receptor down-regulation by glucocorticoids. , 1988, The Journal of biological chemistry.

[21]  L. G. Davis,et al.  Guanidine Isothiocyanate Preparation of Total RNA , 1986 .

[22]  J. Lechner,et al.  A serum-free method for culturing normal human bronchial epithelial cells at clonal density , 1985 .

[23]  M. Karin,et al.  Characterization of DNA sequences through which cadmium and glucocorticoid hormones induce human metallothionein-IIA gene , 1984, Nature.