title: Modulation of transcriptional responses by poly(I:C) and human rhinovirus: effect of long-acting β₂-adrenoceptor agonists.
abstract: Exacerbations of asthma, a chronic inflammatory respiratory disease, are associated with viral upper respiratory tract infections involving human rhinovirus. Although glucocorticoids (corticosteroids) effectively control airways inflammation in many asthmatics, human rhinovirus-associated exacerbations show reduced glucocorticoid responsiveness. Using human bronchial epithelial BEAS-2B cells, we show that human rhinovirus reduced glucocorticoid-inducible activation of glucocorticoid response element (GRE) reporter systems in a time- and concentration-dependent manner. The synthetic double-stranded viral RNA mimetic, polyinosinic:polycytidylic acid (poly(I:C)), also reduced activation of GRE reporter systems in BEAS-2B and pulmonary A549 cells. In addition, poly(I:C) decreased transcription from cAMP response element (CRE)-, TATA-, simian virus 40- and nuclear factor-kappa B (NF-κB)-dependent reporter systems. The effects of poly(I:C) on GRE-reporter activation were countered by the long-acting β2-adrenoceptor agonists, formoterol and salmeterol. Likewise, increased expression of the gene cyclin-dependent kinase inhibitor 1C (CDKN1C; p57(KIP2)) by dexamethasone was reduced by poly(I:C), but was substantially enhanced by the addition of formoterol. Poly(I:C) induced the expression of interleukin-8 (IL8; CXCL8) and this was significantly decreased by dexamethasone, formoterol or their combination. This confirms that not all transcriptional responses were attenuated by poly(I:C) and that decreased glucocorticoid-dependent transcription can be counteracted by the addition of long-acting β2-adrenoceptor agonists. These data show how human rhinovirus may attenuate glucocorticoid-induced transcription to reduce anti-inflammatory activity. However, addition of long-acting β2-adrenoceptor agonist to the glucocorticoid functionally restored this response and shows how glucocorticoid plus long-acting β2-adrenoceptor agonist combinations may prove beneficial during virus-induced exacerbations of asthma.
authors.affiliation: Airways Inflammation Research Group, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, 3330 Hospital Drive NW, AB, Canada T2N 4N1. cfrider@ucalgary.ca
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Rider
authors.forename: Anna
authors.initials: A
authors.lastname: Miller-Larsson
authors.forename: David
authors.initials: D
authors.lastname: Proud
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D004983:Ethanolamines / Q000494:pharmacology*; D000068759:Formoterol Fumarate; D017930:Genes, Reporter; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics; D011070:Poly I-C / Q000494:pharmacology*; D020218:Response Elements; D012229:Rhinovirus; D014158:Transcription, Genetic
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; C493964:CDKN1C protein, human; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004983:Ethanolamines; D005938:Glucocorticoids; D016209:Interleukin-8; D016328:NF-kappa B; D003907:Dexamethasone; D000242:Cyclic AMP; D011070:Poly I-C; D000068759:Formoterol Fumarate