The mitogen-activated protein kinase (MAPK) family is responsible for important signalling pathways which regulate cell activation, differentiation, apoptosis and immune responses. Studies have shown that influenza virus infection activates MAPK family members in mammals. While the extracellular signal-regulated kinase (ERK)1/2 is important for virus replication, activation of p38 controls the expression of RANTES, interleukin (IL)-8 and tumour necrosis factor (TNF)-. In this study, we report that avian influenza virus (AIV) activates ERK, p38 and Jun-N-terminal kinases in avian species. In chicken macrophages, while ERK was required for H9N2 AIV replication, ERK regulated proinflammatory cytokines IL-1, IL-6 and IL-8, which is distinct from what has been previously reported in mammalian cells. Moreover, ERK alone suppressed TNF- and FasL and inhibited TNF-family-mediated extrinsic apoptosis in H9N2-infected chicken macrophages. Taken together, these findings suggest that ERK signalling may uniquely play important roles in avian host responses to AIV infection.


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  1. Badger, A. M., Bradbeer, J. N., Votta, B., Lee, J. C., Adams, J. L. & Griswold, D. E.(1996). Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther 279, 1453–1461. [Google Scholar]
  2. Baldassare, J. J., Bi, Y. & Bellone, C. J.(1999). The role of p38 mitogen-activated protein kinase in IL-1β transcription. J Immunol 162, 5367–5373. [Google Scholar]
  3. Bandyopadhaya, A., Sarkar, M. & Chaudhuri, K.(2008). IL-1β expression in Int407 is induced by flagellin of Vibrio cholerae through TLR5 mediated pathway. Microb Pathog 44, 524–536.[CrossRef] [Google Scholar]
  4. Conze, D., Krahl, T., Kennedy, N., Weiss, L., Lumsden, J., Hess, P., Flavell, R. A., Le Gros, G., Davis, R. J. & Rincon, M.(2002).c-Jun NH2-terminal kinase (JNK)1 and JNK2 have distinct roles in CD8(+) T cell activation. J Exp Med 195, 811–823.[CrossRef] [Google Scholar]
  5. DeSilva, D. R., Feeser, W. S., Tancula, E. J. & Scherle, P. A.(1996). Anergic T cells are defective in both Jun NH2-terminal kinase and mitogen-activated protein kinase signaling pathways. J Exp Med 183, 2017–2023.[CrossRef] [Google Scholar]
  6. Dong, C., Davis, R. J. & Flavell, R. A.(2002). MAP kinases in the immune response. Annu Rev Immunol 20, 55–72.[CrossRef] [Google Scholar]
  7. Garcia, S., Lopez, E. & Lopez-Colome, A. M.(2008). Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms. J Cell Biochem 104, 377–390.[CrossRef] [Google Scholar]
  8. Garrington, T. P. & Johnson, G. L.(1999). Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11, 211–218.[CrossRef] [Google Scholar]
  9. Gaush, C. R. & Smith, T. F.(1968). Replication and plaque assay of influenza virus in an established line of canine kidney cells. Appl Microbiol 16, 588–594. [Google Scholar]
  10. Harper, R. W., Xu, C., Eiserich, J. P., Chen, Y., Kao, C. Y., Thai, P., Setiadi, H. & Wu, R.(2005). Differential regulation of dual NADPH oxidases/peroxidases, Duox1 and Duox2, by Th1 and Th2 cytokines in respiratory tract epithelium. FEBS Lett 579, 4911–4917.[CrossRef] [Google Scholar]
  11. Hayashi, S., Jibiki, I., Asai, Y., Gon, Y., Kobayashi, T., Ichiwata, T., Shimizu, K. & Hashimoto, S.(2008). Analysis of gene expression in human bronchial epithelial cells upon influenza virus infection and regulation by p38 mitogen-activated protein kinase and c-Jun-N-terminal kinase. Respirology 13, 203–214.[CrossRef] [Google Scholar]
  12. Headley, A. S., Tolley, E. & Meduri, G. U.(1997). Infections and the inflammatory response in acute respiratory distress syndrome. Chest 111, 1306–1321.[CrossRef] [Google Scholar]
  13. Hirst, G. K.(1948). The nature of hemagglutination by viruses. Harvey Lect 44, 84–98. [Google Scholar]
  14. Kujime, K., Hashimoto, S., Gon, Y., Shimizu, K. & Horie, T.(2000). p38 mitogen-activated protein kinase and c-Jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells. J Immunol 164, 3222–3228.[CrossRef] [Google Scholar]
  15. Lee, J. C. & Adams, J. L.(1995). Inhibitors of serine/threonine kinases. Curr Opin Biotechnol 6, 657–661.[CrossRef] [Google Scholar]
  16. Lee, D. C., Cheung, C. Y., Law, A. H., Mok, C. K., Peiris, M. & Lau, A. S.(2005). p38 mitogen-activated protein kinase-dependent hyperinduction of tumor necrosis factor alpha expression in response to avian influenza virus H5N1. J Virol 79, 10147–10154.[CrossRef] [Google Scholar]
  17. Leonard, M., Ryan, M. P., Watson, A. J., Schramek, H. & Healy, E.(1999). Role of MAP kinase pathways in mediating IL-6 production in human primary mesangial and proximal tubular cells. Kidney Int 56, 1366–1377.[CrossRef] [Google Scholar]
  18. Ludwig, S., Ehrhardt, C., Neumeier, E. R., Kracht, M., Rapp, U. R. & Pleschka, S.(2001). Influenza virus-induced AP-1-dependent gene expression requires activation of the JNK signaling pathway. J Biol Chem 276, 10990–10998.[CrossRef] [Google Scholar]
  19. Ludwig, S., Planz, O., Pleschka, S. & Wolff, T.(2003). Influenza-virus-induced signaling cascades: targets for antiviral therapy? Trends Mol Med 9, 46–52.[CrossRef] [Google Scholar]
  20. Ludwig, S., Wolff, T., Ehrhardt, C., Wurzer, W. J., Reinhardt, J., Planz, O. & Pleschka, S.(2004). MEK inhibition impairs influenza B virus propagation without emergence of resistant variants. FEBS Lett 561, 37–43.[CrossRef] [Google Scholar]
  21. Ludwig, S., Pleschka, S., Planz, O. & Wolff, T.(2006). Ringing the alarm bells: signalling and apoptosis in influenza virus infected cells. Cell Microbiol 8, 375–386.[CrossRef] [Google Scholar]
  22. Mandal, C., Dutta, A., Mallick, A., Chandra, S., Misra, L. & Sangwan, R. S.(2008). Withaferin A induces apoptosis by activating p38 mitogen-activated protein kinase signaling cascade in leukemic cells of lymphoid and myeloid origin through mitochondrial death cascade. Apoptosis 13, 1450–1464.[CrossRef] [Google Scholar]
  23. Marjuki, H., Yen, H. L., Franks, J., Webster, R. G., Pleschka, S. & Hoffmann, E.(2007). Higher polymerase activity of a human influenza virus enhances activation of the hemagglutinin-induced Raf/MEK/ERK signal cascade. Virol J 4, 134[CrossRef] [Google Scholar]
  24. Mori, I., Goshima, F., Koshizuka, T., Koide, N., Sugiyama, T., Yoshida, T., Yokochi, T., Nishiyama, Y. & Kimura, Y.(2003). Differential activation of the c-Jun N-terminal kinase/stress-activated protein kinase and p38 mitogen-activated protein kinase signal transduction pathways in the mouse brain upon infection with neurovirulent influenza A virus. J Gen Virol 84, 2401–2408.[CrossRef] [Google Scholar]
  25. Pearson, G., Robinson, F., Beers Gibson, T., Xu, B. E., Karandikar, M., Berman, K. & Cobb, M. H.(2001). Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev 22, 153–183. [Google Scholar]
  26. Pleschka, S., Wolff, T., Ehrhardt, C., Hobom, G., Planz, O., Rapp, U. R. & Ludwig, S.(2001). Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. Nat Cell Biol 3, 301–305.[CrossRef] [Google Scholar]
  27. Rath, N. C., Parcells, M. S., Xie, H. & Santin, E.(2003). Characterization of a spontaneously transformed chicken mononuclear cell line. Vet Immunol Immunopathol 96, 93–104.[CrossRef] [Google Scholar]
  28. Spackman, E., Senne, D. A., Bulaga, L. L., Myers, T. J., Perdue, M. L., Garber, L. P., Lohman, K., Daum, L. T. & Suarez, D. L.(2003). Development of real-time RT-PCR for the detection of avian influenza virus. Avian Dis 47, 1079–1082.[CrossRef] [Google Scholar]
  29. Sternsdorf, T., Jensen, K., Zuchner, D. & Will, H.(1997). Cellular localization, expression, and structure of the nuclear dot protein 52. J Cell Biol 138, 435–448.[CrossRef] [Google Scholar]
  30. To, K. F., Chan, P. K., Chan, K. F., Lee, W. K., Lam, W. Y., Wong, K. F., Tang, N. L., Tsang, D. N., Sung, R. Y. & other authors(2001). Pathology of fatal human infection associated with avian influenza A H5N1 virus. J Med Virol 63, 242–246.[CrossRef] [Google Scholar]
  31. Uchide, N., Ohyama, K., Bessho, T. & Toyoda, H.(2005). Induction of pro-inflammatory cytokine gene expression and apoptosis in human chorion cells of fetal membranes by influenza virus infection: possible implications for maintenance and interruption of pregnancy during infection. Med Sci Monit 11, RA7–RA16. [Google Scholar]
  32. Woolcock, P. R., McFarland, M. D., Lai, S. & Chin, S.(2001). Enhanced recovery of avian influenza virus isolates by a combination of chicken embryo inoculation methods. Avian Dis 45, 1030–1035.[CrossRef] [Google Scholar]
  33. Xing, Z., Conway, E. M., Kang, C. & Winoto, A.(2004). Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis. J Exp Med 199, 69–80. [Google Scholar]
  34. Xing, Z., Cardona, C., Dao, P., Crossley, B., Hietala, S. & Boyce, W.(2008a). Inability of real-time reverse transcriptase PCR assay to detect subtype H7 avian influenza viruses isolated from wild birds. J Clin Microbiol 46, 1844–1846.[CrossRef] [Google Scholar]
  35. Xing, Z., Cardona, C. J., Li, J., Dao, N., Tran, T. & Andrada, J.(2008b). Modulation of the immune responses in chickens by low-pathogenicity avian influenza virus H9N2. J Gen Virol 89, 1288–1299.[CrossRef] [Google Scholar]
  36. Xing, Z., Cardona, C. J., Adams, S., Yang, Z., Li, J., Perez, D. & Woolcock, P.(2009). Differential regulation of antiviral and proinflammatory cytokines and suppression of Fas-mediated apoptosis by NS1 of H9N2 avian influenza virus in chicken macrophages. J Gen Virol 90, 1109–1118.[CrossRef] [Google Scholar]
  37. Zhu, J., Wu, X., Goel, S., Gowda, N. M., Kumar, S., Krishnegowda, G., Mishra, G., Weinberg, R., Li, G. & other authors(2009). MAPK-activated protein kinase 2 differentially regulates Plasmodium falciparum glycosylphosphatidylinositol induced production of TNF-α and IL-12 in macrophages. J Biol Chem 284, 15750–15761.[CrossRef] [Google Scholar]

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