title: Retinoic acid inducible gene-I and mda-5 are involved in influenza A virus-induced expression of antiviral cytokines.
abstract: Activation of host cell antiviral responses is mediated by pattern recognition receptors. Cytoplasmic RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (mda-5) have been identified to function as receptors for double-stranded RNA. Here we show that interferon (IFN)-alpha pretreatment enhances influenza A virus-induced expression of IFN-alpha, IFN-beta, interleukin (IL)-28 and IL-29 genes in human dendritic cells and epithelial cell lines. Both IFN-alpha and IFN-beta strongly enhanced RIG-I and mda-5 mRNA and protein expression in these cell types. Expression of RIG-I and mda-5 gene constructs, but not that of TLR3, lead to a dramatic enhancement of IFN-beta promoter driven transcription in influenza A virus-infected epithelial cells. Furthermore, dominant negative RIG-I gene construct inhibited influenza A virus-induced IFN-beta promoter activity. In conclusion, our results show that in epithelial cells influenza A virus-induced antiviral cytokine gene expression is triggered by RIG-I and mda-5, whose expression is positively regulated by IFN-alpha.
authors.affiliation: Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Sirén
authors.forename: Tadaatsu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Taija
authors.initials: T
authors.lastname: Pietilä
authors.forename: Diana L
authors.initials: DL
authors.lastname: Noah
authors.forename: Rongtuan
authors.initials: R
authors.lastname: Lin
authors.forename: John
authors.initials: J
authors.lastname: Hiscott
authors.forename: Robert M
authors.initials: RM
authors.lastname: Krug
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
mesh_terms: D016207:Cytokines / Q000096:biosynthesis*; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D005786:Gene Expression Regulation; D006801:Humans; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D000072640:Interferon-Induced Helicase, IFIH1; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D016207:Cytokines; D011506:Proteins; C431552:RAI1 protein, human; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C452815:IFIH1 protein, human; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1