title: Inhibition of Jak1-dependent signal transduction in airway epithelial cells infected with adenovirus.
abstract: Adenoviral evolution has generated mechanisms to resist host cell defense systems, but the biochemical basis for evasion of multiple antiviral pathways in the airway by adenoviruses is incompletely understood. We hypothesized that adenoviruses modulate airway epithelial responses to type I interferons by altering the levels and activation of specific Janus family kinase-signal transducer and activator of transcription (JAK-STAT) signaling components. In this study, specific effects of adenovirus type 5 (AdV) on selected JAK-STAT signal transduction pathways were identified in human tracheobronchial epithelial cells, with focus on type I interferon-dependent signaling and gene expression. We found that wild-type AdV infection inhibited IFN-alpha-induced expression of antiviral proteins in epithelial cells by blocking phosphorylation of the Stat1 and Stat2 transcription factors that are required for activation of type I interferon-dependent genes. These effects correlated with AdV-induced down-regulation of expression of the receptor-associated tyrosine kinase Jak1 through a decrease in Jak1 mRNA levels. Phosphorylation of Stat3 in response to IL-6 and oncostatin M was also lost in AdV-infected cells, indicating loss of epithelial cell responses to other cytokines that depend on Jak1. In contrast, IL-4- and IL-13-dependent phosphorylation of Stat6 was not affected during AdV infection, indicating that the virus modulates specific signaling pathways, as these Stat6-activating pathways can function independent of Jak1. Taken together, the results indicate that AdV down-regulates host epithelial cell Jak1 to assure inhibition of the antiviral effects of multiple mediators to subvert airway defense responses and establish a productive infection.
authors.affiliation: Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.forename: Murali
authors.initials: M
authors.lastname: Ramaswamy
authors.forename: Lori J
authors.initials: LJ
authors.lastname: Manzel
authors.forename: Dwight C
authors.initials: DC
authors.lastname: Look
mesh_terms: D000256:Adenoviridae / Q000187:drug effects / Q000378:metabolism*; D000257:Adenoviridae Infections / Q000201:enzymology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism / Q000821:virology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016898:Interferon-alpha; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D053613:Janus Kinase 1