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).