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Journal of Virology, April 2006, p. 3515-3522, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3515-3522.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tumor Necrosis Factor Alpha Enhances Influenza A Virus-Induced Expression of Antiviral Cytokines by Activating RIG-I Gene Expression

Sampsa Matikainen,1* Jukka Sirén,1 Jorma Tissari,2 Ville Veckman,1 Jaana Pirhonen,1 Martina Severa,3,4 Qiang Sun,5 Rongtuan Lin,5 Seppo Meri,2 Gilles Uzé,4 John Hiscott,5 and Ilkka Julkunen1

Department of Viral Diseases and Immunology, National Public Health Institute, Helsinki, Finland,1 Haartman Institute, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland,2 Department of Infectious, Parasitic, and Immunomediated Diseases, Istituto Superiore di Sanità, Rome, Italy,3 Centre National de la Recherche Scientifique, Institute of Molecular Genetics, Montpellier, France,4 McGill University, Montreal, Canada5

Received 1 June 2005/ Accepted 8 November 2005

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-ß, 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-ß, 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{varepsilon} mRNA and protein expression. Ectopic expression of a constitutively active form of RIG-I ({Delta}RIG-I) or IKK{varepsilon}, but not that of TLR3, enhanced the expression of the IFN-ß, IL-28, and IL-29 genes. Furthermore, a dominant-negative form of RIG-I inhibited influenza A virus-induced IFN-ß 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.

* Corresponding author. Present address: Unit of Excellence in Immunotoxicology, Finnish Institute of Occupational Health (FIOH), Topeliuksenkatu 41b, 00250 Helsinki, Finland. Phone: 358-30-4742592. Fax: 358-30-4742116. E-mail: sampsa.matikainen{at}ttl.fi.

Journal of Virology, April 2006, p. 3515-3522, Vol. 80, No. 7
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.7.3515-3522.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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