Open Accessp38 Mitogen-Activated Protein Kinase-Dependent Hyperinduction of Tumor Necrosis Factor Alpha Expression in Response to Avian Influenza Virus H5N1
Author(s) -
Davy C. W. Lee,
Chi-Wai Cheung,
Anna H.Y. Law,
Chris K. P. Mok,
Malik Peiris,
Alexander Lau
Publication year - 2005
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.79.16.10147-10154.2005
Subject(s) - biology , influenza a virus subtype h5n1 , virology , tumor necrosis factor alpha , protein kinase a , p38 mitogen activated protein kinases , virus , influenza a virus , kinase , avian influenza virus , mitogen activated protein kinase , alpha (finance) , protein kinase r , microbiology and biotechnology , immunology , mitogen activated protein kinase kinase , medicine , construct validity , nursing , patient satisfaction
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-kappaB and cellular kinases in TNF-alpha dysregulation. H5N1 and H1N1 viruses did not differ in the activation of NF-kappaB or degradation of IkappaB-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.