title: Influenza induces IL-8 and GM-CSF secretion by human alveolar epithelial cells through HGF/c-Met and TGF-α/EGFR signaling.
abstract: The most severe complication of influenza is viral pneumonia, which can lead to the acute respiratory distress syndrome. Alveolar epithelial cells (AECs) are the first cells that influenza virus encounters upon entering the alveolus. Infected epithelial cells produce cytokines that attract and activate neutrophils and macrophages, which in turn induce damage to the epithelial-endothelial barrier. Hepatocyte growth factor (HGF)/c-Met and transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) are well known to regulate repair of damaged alveolar epithelium by stimulating cell migration and proliferation. Recently, TGF-α/EGFR signaling has also been shown to regulate innate immune responses in bronchial epithelial cells. However, little is known about whether HGF/c-Met signaling alters the innate immune responses and whether the innate immune responses in AECs are regulated by HGF/c-Met and TGF-α/EGFR. We hypothesized that HGF/c-Met and TGF-α/EGFR would regulate innate immune responses to influenza A virus infection in human AECs. We found that recombinant human HGF (rhHGF) and rhTGF-α stimulated primary human AECs to secrete IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF) strongly and IL-6 and monocyte chemotactic protein 1 moderately. Influenza infection stimulated the secretion of IL-8 and GM-CSF by AECs plated on rat-tail collagen through EGFR activation likely by TGF-α released from AECs and through c-Met activated by HGF secreted from lung fibroblasts. HGF secretion by fibroblasts was stimulated by AEC production of prostaglandin E2 during influenza infection. We conclude that HGF/c-Met and TGF-α/EGFR signaling enhances the innate immune responses by human AECs during influenza infections.
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado; masonb@njhealth.org.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado;
authors.forename: Kelly
authors.initials: K
authors.lastname: Correll
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado; Department of Medicine, University of Colorado, Aurora, Colorado;
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Zemans
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado;
authors.forename: Christina C
authors.initials: CC
authors.lastname: Leslie
authors.affiliation: Department of Pharmacology, University of Colorado, Aurora, Colorado.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Murphy
authors.affiliation: Department of Medicine, National Jewish Health, Denver, Colorado; Department of Medicine, University of Colorado, Aurora, Colorado;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mason
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D016209:Interleukin-8 / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000473:pathology; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism
chemical_list: C066855:HGF protein, human; D016209:Interleukin-8; D016211:Transforming Growth Factor alpha; D017228:Hepatocyte Growth Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D015232:Dinoprostone
keywords: alveolar epithelial cells; hepatocyte growth factor/c-Met; influenza; innate immune responses; transforming growth factor-α/epidermal growth factor receptor