Modulation of epidermal growth factor receptor binding to human airway smooth muscle cells by glucocorticoids and beta2-adrenergic receptor agonists.
EGF receptors (EGFRs) are increased in airway smooth muscle in asthma, which may contribute to both their hyperproliferation and hypercontractility. Lysophosphatidic acid (LPA) is a candidate pathological agent in asthma and other airway diseases, and LPA upregulates EGFRs in human airway smooth muscle (HASM) cells. We tested whether therapeutic glucocorticoids and/or beta(2)-adrenergic receptor (beta(2)AR) agonists also alter EGFR binding in HASM cells. Exposure to glucocorticoids for 24 h induced a twofold increase in EGFR binding similar to that with LPA; fluticasone was markedly more potent than dexamethasone. The increase in EGFR binding by glucocorticoids required 24-h exposure, consistent with transcription-mediated effects. Although the increase in EGFR binding was blocked by the protein synthesis inhibitor cycloheximide for LPA, fluticasone, and dexamethasone, only LPA induced a significant increase in EGFR protein expression detected by immunoblotting. In contrast to the increased binding induced by the glucocorticoids, the beta(2)AR agonists isoproterenol, albuterol, and salmeterol all induced a decrease in EGFR binding. beta(2)AR agonist effects were multiphasic, with an initial decline at 2-4 h that reversed by 6 h and a second, somewhat greater decrease by 18-24 h. In cells pretreated with glucocorticoids, the decreases in EGFR binding by subsequent beta(2)AR treatment were not statistically significant; glucocorticoid upregulation of EGFRs also prevented further increases by LPA. Similar increases by glucocorticoids and decreases by beta(2)AR agonists were found in HFL-1 human lung fibroblasts. These complex and opposing effects of clinically relevant glucocorticoids and beta(2)AR agonists on airway mesenchymal cell EGFRs likely contribute to their overall therapeutic profile in the diseased airway.
Kassel
Karen M
KM
Department of Pharmacology and Experimental Neuroscience, 985800 Nebraska Medical Center, Omaha, NE 68198-5800, USA.
Schulte
Nancy A
NA
Toews
Myron L
ML
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000068298:Fluticasone; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000166:cytology*; D008246:Lysophospholipids / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D013997:Time Factors
D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D005938:Glucocorticoids; D008246:Lysophospholipids; D003907:Dexamethasone; D003513:Cycloheximide; D000068298:Fluticasone; D066246:ErbB Receptors; C032881:lysophosphatidic acid