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Reactive Oxygen Species Induce Antiviral Innate Immune Response through IFN-λ Regulation in Human Nasal Epithelial Cells

 Hyun Jik Kim  ;  Chang-Hoon Kim  ;  Ji-Hwan Ryu  ;  Min-Ji Kim  ;  Chong Yoon Park  ;  Jae Myun Lee  ;  Michael J. Holtzman  ;  Joo-Heon Yoon 
 American Journal of Respiratory Cell and Molecular Biology, Vol.49(5) : 855-865, 2013 
Journal Title
 American Journal of Respiratory Cell and Molecular Biology 
Issue Date
Animals ; Dogs ; Dual Oxidases ; Epithelial Cells/drug effects ; Epithelial Cells/immunology ; Epithelial Cells/metabolism* ; Epithelial Cells/virology ; Free Radical Scavengers/pharmacology ; Host-Pathogen Interactions ; Humans ; Immunity, Innate*/drug effects ; Interferon-beta/metabolism ; Interferon-gamma/genetics ; Interferon-gamma/metabolism* ; Madin Darby Canine Kidney Cells ; Mitochondria/immunology ; Mitochondria/metabolism ; Mitochondria/virology ; NADPH Oxidases/metabolism ; Nasal Mucosa/drug effects ; Nasal Mucosa/immunology ; Nasal Mucosa/metabolism* ; Nasal Mucosa/virology ; Orthomyxoviridae/genetics ; Orthomyxoviridae/immunology* ; Orthomyxoviridae/pathogenicity ; Oxidative Stress*/drug effects ; RNA, Messenger/metabolism ; RNA, Viral/metabolism ; Reactive Oxygen Species/metabolism* ; Signal Transduction ; Time Factors ; Up-Regulation
influenza A virus ; IFN-λ ; reactive oxygen species ; mitochondria ; Duox2
This study sought to explore the role of the IFN-related innate immune responses (IFN-β and IFN-λ) and of reactive oxygen species (ROS) after influenza A virus (IAV) infection for antiviral innate immune activity in normal human nasal epithelial (NHNE) cells that are highly exposed to IAV. Passage-2 NHNE cells were inoculated with the IAV WSN/33 for 1, 2, and 3 days to assess the capacity of IFN and the relationship between ROS generation and IFN-λ secretion for controlling IAV infection. Viral titers and IAV mRNA levels increased after infection. In concert with viral titers, we found that the generation of IFNs, such as IFN-β, IFN-λ1, and IFN-λ2/3, was induced after IAV infection until 3 days after infection. The induction of IFN-λ gene expression and protein secretion may be predominant after IAV infection. Similarly, we observed that intracellular ROS generation increased 60 minutes after IAV infection. Viral titers and mRNA levels of IAV were significantly higher in cases with scavenging ROS, in cases with an induced IFN-λ mRNA level, or where the secreted protein concentration of IFN-λ was attenuated after the suppression of ROS generation. Both mitochondrial and dual oxidase (Doux)2-generated ROS were correlated with IAV mRNA and viral titers. The inhibition of mitochondrial ROS generation and the knockdown of Duox2 gene expression highly increased IAV viral titers and decreased IFN-λ secretion. Our findings suggest that the production of ROS may be responsible for IFN-λ secretion to control IAV infection. Both mitochondria and Duox2 are possible sources of ROS generation, which is required to initiate an innate immune response in NHNE cells.
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Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
5. Research Institutes (연구소) > Research Center for Human Natural Defense System (생체방어연구센터) > 1. Journal Papers
Yonsei Authors
Kim, Min Ji(김민지)
Kim, Chang Hoon(김창훈) ORCID logo https://orcid.org/0000-0003-1238-6396
Ryu, Ji Hwan(유지환)
Yoon, Joo Heon(윤주헌)
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
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