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Journal of Virology, August 2005, p. 10147-10154, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10147-10154.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

p38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1

Davy C. W. Lee,1 Chung-Yan Cheung,2 Anna H. Y. Law,1 Chris K. P. Mok,1 Malik Peiris,2 and Allan S. Y. Lau1*

Immunology Research Laboratory, Department of Paediatrics and Adolescent Medicine,1 Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China2

Received 2 December 2004/ Accepted 25 May 2005

Avian influenza A virus subtype H5N1 can infect humans to cause a severe viral pneumonia with mortality rates of more than 30%. The biological basis for this unusual disease severity is not fully understood. We previously demonstrated that in contrast to human influenza A virus subtypes including H1N1 or H3N2, the H5N1 virus associated with the "bird flu" outbreak in Hong Kong in 1997 (H5N1/97) hyperinduces proinflammatory cytokines, including tumor necrosis factor alpha (TNF-{alpha}), in primary human macrophages in vitro. To delineate the molecular mechanisms involved, we analyzed the role of transcription factor NF-{kappa}B and cellular kinases in TNF-{alpha} dysregulation. H5N1 and H1N1 viruses did not differ in the activation of NF-{kappa}B or degradation of I{kappa}B-{alpha} in human macrophages. However, we demonstrated that unlike H1N1 virus, H5N1/97 strongly activates mitogen-activated protein kinase (MAPK), including p38 MAPK and extracellular signal-regulated kinases 1 and 2. Specific inhibitors of p38 MAPK significantly reduced the H5N1/97-induced TNF-{alpha} expression in macrophages. Taken together, our findings suggest that H5N1/97-mediated hyperinduction of cytokines involves the p38 MAPK signaling pathway. These results may provide insights into the pathogenesis of H5N1 disease and rationales for the development of novel therapeutic strategies.

* Corresponding author. Mailing address: Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong Special Administrative Region, People's Republic of China. Phone: 852-2855-4269. Fax: 852-2855-1523. E-mail: asylau{at}hku.hk.

Journal of Virology, August 2005, p. 10147-10154, Vol. 79, No. 16
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.16.10147-10154.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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