title: Airway epithelial epidermal growth factor receptor mediates hogbarn dust-induced cytokine release but not Ca2+ response.
abstract: A subset of workers in swine confinement facilities develops chronic respiratory disease. An aqueous extract of dust from these facilities (hogbarn dust extract [HDE]) induces IL-6 and IL-8 release and several other responses in isolated airway epithelial cells. The cell membrane receptors by which HDE initiates these responses have not been identified. Because several other inhaled agents induce airway epithelial cell responses through epidermal growth factor receptor (EGFR) activation, we hypothesized that HDE would activate EGFRs and that EGFRs would be required for some of the responses to HDE. Exposure of Beas-2B cells to HDE caused EGFR phosphorylation and downstream ERK activation, and both responses were blocked by the EGFR-selective kinase inhibitor AG1478. AG1478 and EGFR-neutralizing antibody reduced HDE-stimulated IL-6 and IL-8 release by about half. Similar EGFR phosphorylation and requirement of EGFRs for maximal IL-6 and IL-8 release were found with primary isolates of human bronchial epithelial cells. Because HDE-stimulated IL-6 and IL-8 release involve the Ca(2+)-dependent protein kinase Cα, we hypothesized that HDE would induce intracellular Ca(2+) mobilization. HDE exposure induced intracellular Ca(2+) mobilization in Beas-2B cells and in primary cell isolates, but this response was neither mimicked by EGF nor inhibited by AG1478. Thus, HDE activates EGFRs and their downstream signaling, and EGFR activation is required for some but not all airway epithelial cell responses to HDE.
authors: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA.
authors: Puttappa R
authors: PR
authors: Dodmane
authors: Nancy A
authors: NA
authors: Schulte
authors: Art J
authors: AJ
authors: Heires
authors: Hamid
authors: H
authors: Band
authors: Debra J
authors: DJ
authors: Romberger
authors: Myron L
authors: ML
authors: Toews
mesh_terms: D000395:Air Pollutants, Occupational / Q000633:toxicity*; D000822:Animal Husbandry; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004391:Dust; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013552:Swine; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000395:Air Pollutants, Occupational; D057134:Antibodies, Neutralizing; C508606:CXCL8 protein, human; D016207:Cytokines; D004391:Dust; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium