Tumor necrosis factor alpha enhances influenza A virus-induced expression of antiviral cytokines by activating RIG-I gene expression.
Epithelial cells of the lung are the primary targets for respiratory viruses. Virus-carried single-stranded RNA (ssRNA) can activate Toll-like receptors (TLRs) 7 and 8, whereas dsRNA is bound by TLR3 and a cytoplasmic RNA helicase, retinoic acid-inducible protein I (RIG-I). This recognition leads to the activation of host cell cytokine gene expression. Here we have studied the regulation of influenza A and Sendai virus-induced alpha interferon (IFN-alpha), IFN-beta, interleukin-28 (IL-28), and IL-29 gene expression in human lung A549 epithelial cells. Sendai virus infection readily activated the expression of the IFN-alpha, IFN-beta, IL-28, and IL-29 genes, whereas influenza A virus-induced activation of these genes was mainly dependent on pretreatment of A549 cells with IFN-alpha or tumor necrosis factor alpha (TNF-alpha). IFN-alpha and TNF-alpha induced the expression of the RIG-I, TLR3, MyD88, TRIF, and IRF7 genes, whereas no detectable TLR7 and TLR8 was seen in A549 cells. TNF-alpha also strongly enhanced IKK epsilon mRNA and protein expression. Ectopic expression of a constitutively active form of RIG-I (deltaRIG-I) or IKK epsilon, but not that of TLR3, enhanced the expression of the IFN-beta, IL-28, and IL-29 genes. Furthermore, a dominant-negative form of RIG-I inhibited influenza A virus-induced IFN-beta promoter activity in TNF-alpha-pretreated cells. In conclusion, IFN-alpha and TNF-alpha enhanced the expression of the components of TLR and RIG-I signaling pathways, but RIG-I was identified as the central regulator of influenza A virus-induced expression of antiviral cytokines in human lung epithelial cells.
Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland. sampsa.matikainen@ttl.fi
Sampsa
S
Matikainen
Jukka
J
Sirén
Jorma
J
Tissari
Ville
V
Veckman
Jaana
J
Pirhonen
Martina
M
Severa
Qiang
Q
Sun
Rongtuan
R
Lin
Seppo
S
Meri
Gilles
G
Uzé
John
J
Hiscott
Ilkka
I
Julkunen
D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation; D006801:Humans; D009980:Influenza A virus / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000494:pharmacology; D016899:Interferon-beta / Q000235:genetics / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D007700:Kinetics; D020365:RNA Helicases / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D029082:Sendai virus / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D016898:Interferon-alpha; D007378:Interleukins; C437968:PLAAT4 protein, human; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D020365:RNA Helicases