Cigarette smoke suppresses type I interferon-mediated antiviral immunity in lung fibroblast and epithelial cells.
The objective of this study was to investigate the impact of cigarette smoke on innate antiviral defense mechanisms; specifically, we examined the effects of cigarette smoke on the induction of type I interferon (IFN). We observed a dose-dependent decrease in the ability of human lung fibroblast and epithelial cells to elicit an antiviral response against a viral double-strand RNA (dsRNA) mimic, polyI:C, in the presence of cigarette smoke-conditioned medium (SCM). Mechanistically, SCM decreases the expression of IFN-stimulated gene 15 (ISG15) and IFN regulatory factor-7 (IRF-7) transcripts and suppresses the nuclear translocation of key transcription factors, nuclear factor-kappaB (NF-kappaB) and IRF-3, after polyI:C stimulation. Furthermore, we provide evidence that the intercellular defense strategy against viral infection is also impaired. We observed a decrease in the ability of fibroblasts to elicit an antiviral state in response to IFN-beta stimulation. This was associated with decreased nuclear translocation of phosphorylated Stat1 in response to IFN-beta treatment. The effects elicited by SCM are reversible and are almost entirely abrogated in the presence of an antioxidant, such as glutathione. Our findings suggest that cigarette smoke affects the immediate-early, inductive, and amplification phases of the type I IFN response.
Bauer
Carla M T
CM
The Centre for Gene Therapeutics, Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.
Dewitte-Orr
Stephanie J
SJ
Hornby
Kyle R
KR
Zavitz
Caleb C J
CC
Lichty
Brian D
BD
Stämpfli
Martin R
MR
Mossman
Karen L
KL
D000998:Antiviral Agents / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology* / Q000378:metabolism; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007113:Immunity, Innate; D007369:Interferon Inducers / Q000494:pharmacology; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana; D014452:Ubiquitins / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D000998:Antiviral Agents; D017077:Culture Media, Conditioned; D016207:Cytokines; D005978:Glutathione; D007369:Interferon Inducers; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D011070:Poly I-C; D017346:Protein Serine-Threonine Kinases; D050794:STAT1 Transcription Factor; D012906:Smoke; D014452:Ubiquitins; D000097782:NF-kappaB-Inducing Kinase; C494232:IRF3 protein, human; C494234:IRF7 protein, human; C494079:STAT1 protein, human; C074034:ISG15 protein, human