title: Influenza induces endoplasmic reticulum stress, caspase-12-dependent apoptosis, and c-Jun N-terminal kinase-mediated transforming growth factor-β release in lung epithelial cells.
abstract: Influenza A virus (IAV) infection is known to induce endoplasmic reticulum (ER) stress, Fas-dependent apoptosis, and TGF-β production in a variety of cells. However, the relationship between these events in murine primary tracheal epithelial cells (MTECS), which are considered one of the primary sites of IAV infection and replication, is unclear. We show that IAV infection induced ER stress marker activating transcription factor-6 and endoplasmic reticulum protein 57-kD (ERp57), but not C/EBP homologous protein (CHOP). In contrast, the ER stress inducer thapsigargin (THP) increased CHOP. IAV infection activated caspases and apoptosis, independently of Fas and caspase-8, in MTECs. Instead, apoptosis was mediated by caspase-12. A decrease in ERp57 attenuated the IAV burden and decreased caspase-12 activation and apoptosis in epithelial cells. TGF-β production was enhanced in IAV-infected MTECs, compared with THP or staurosporine. IAV infection caused the activation of c-Jun N-terminal kinase (JNK). Furthermore, IAV-induced TGF-β production required the presence of JNK1, a finding that suggests a role for JNK1 in IAV-induced epithelial injury and subsequent TGF-β production. These novel findings suggest a potential mechanistic role for a distinct ER stress response induced by IAV, and a profibrogenic/repair response in contrast to other pharmacological inducers of ER stress. These responses may also have a potential role in acute lung injury, fibroproliferative acute respiratory distress syndrome, and the recently identified H1N1 influenza-induced exacerbations of chronic obstructive pulmonary disease (Wedzicha JA. Proc Am Thorac Soc 2004;1:115-120) and idiopathic pulmonary fibrosis (Umeda Y, et al. Int Med 2010;49:2333-2336).
authors.affiliation: Department of Pathology, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Elle C
authors.initials: EC
authors.lastname: Roberson
authors.forename: Jane E
authors.initials: JE
authors.lastname: Tully
authors.forename: Amy S
authors.initials: AS
authors.lastname: Guala
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Reiss
authors.forename: Karolyn E
authors.initials: KE
authors.lastname: Godburn
authors.forename: Derek A
authors.initials: DA
authors.lastname: Pociask
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.forename: Oliver
authors.initials: O
authors.lastname: Dienz
authors.forename: Yvonne M W
authors.initials: YM
authors.lastname: Janssen-Heininger
authors.forename: Vikas
authors.initials: V
authors.lastname: Anathy
mesh_terms: D000818:Animals; D017209:Apoptosis; D053454:Caspase 12 / Q000378:metabolism; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000473:pathology; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology / Q000821:virology; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D019562:Viral Load
chemical_list: D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D019284:Thapsigargin; D048031:JNK Mitogen-Activated Protein Kinases; D053454:Caspase 12; D019311:Staurosporine