title: Agonist-induced β2-adrenoceptor desensitization and downregulation enhance pro-inflammatory cytokine release in human bronchial epithelial cells.
abstract: It is not clear whether increased asthma severity associated with long-term use of β2-adrenoceptor (β2-AR) agonists can be attributed to receptor degradation and increased inflammation. We investigated the cross-talk between β-AR agonist-mediated effects on β2-AR function and expression and cytokine release in human bronchial epithelial cells. In 16HBE14o(-) cells grown in the presence and absence of β-AR agonists and/or antagonists, the β2-AR density was assessed by radioligand binding; the receptor protein and mRNA was determined using laser scanning cytometer and RT-PCR; cAMP generation, the cytokines IL-6 and IL-8 release were determined using AlphaScreen Assay and ELISA, respectively. Isoprenaline (ISO) and salbutamol (Salbu) induced a concentration- and time-dependent significant decrease in β2-AR density. Both Salbu and ISO reduced cAMP generation in a concentration-dependent manner while in same cell culture the IL-6 and IL-8 release was significantly enhanced. These effects were antagonized to a greater extent by ICI 118.551 than by propranolol, but CGP 20712A had no effect. Reduction of the β2-AR protein and mRNA could be seen when cells were treated with ISO for 24 h. Our findings indicate a direct link between cytokine release and altered β2-AR expression and function in airway epithelial cells. β2-AR desensitization and downregulation induced by long-term treatment with β2-AR agonists during asthma may account for adverse reactions also due to enhanced release of pro-inflammatory mediators and should, thus, be considered in asthma therapy.
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Oehme
authors.affiliation: Department of Paediatric Cardiology, Heart Centre and Translational Centre Regenerative Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Mittag
authors.affiliation: Institute of Bacteriology and Mycology, University of Leipzig, Leipzig, Germany.
authors.forename: Wieland
authors.initials: W
authors.lastname: Schrödl
authors.affiliation: Department of Paediatric Cardiology, Heart Centre and Translational Centre Regenerative Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Attila
authors.initials: A
authors.lastname: Tarnok
authors.affiliation: Institute of Pharmacy, University of Leipzig, Leipzig, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Nieber
authors.affiliation: Institute of Pharmacology, Pharmacy and Toxicology, University of Leipzig, An den Tierkliniken 15, 04103 Leipzig, Germany. Electronic address: gabraham@rz.uni-leipzig.de.
authors.forename: Getu
authors.initials: G
authors.lastname: Abraham
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000008:administration & dosage / Q000494:pharmacology*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007545:Isoproterenol / Q000008:administration & dosage / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D000319:Adrenergic beta-Antagonists; D016207:Cytokines; D018836:Inflammation Mediators; D015850:Interleukin-6; D016209:Interleukin-8; D011412:Propanolamines; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; D011433:Propranolol; D000242:Cyclic AMP; D007545:Isoproterenol; D000420:Albuterol
keywords: Asthma; Bronchial epithelial cells; cAMP; β(2)-agonists; β-adrenoceptors