This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nakamichi, K. Articles by Kurane, I. Search for Related Content PubMed PubMed Citation Articles by Nakamichi, K. Articles by Kurane, I.

 Previous Article  |  Next Article 

Journal of Virology, September 2004, p. 9376-9388, Vol. 78, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.17.9376-9388.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

Department of Virology I,¹ Department of Veterinary Science, National Institute of Infectious Diseases, Toyama, Shinjuku, Tokyo, Japan²

Received 23 February 2004/ Accepted 29 April 2004

Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.

This article has been cited by other articles:

• Gholami, A., Kassis, R., Real, E., Delmas, O., Guadagnini, S., Larrous, F., Obach, D., Prevost, M.-C., Jacob, Y., Bourhy, H. (2008). Mitochondrial Dysfunction in Lyssavirus-Induced Apoptosis. J. Virol. 82: 4774-4784 [Abstract] [Full Text]  
• Granja, A. G., Sabina, P., Salas, M. L., Fresno, M., Revilla, Y. (2006). Regulation of Inducible Nitric Oxide Synthase Expression by Viral A238L-Mediated Inhibition of p65/RelA Acetylation and p300 Transactivation.. J. Virol. 80: 10487-10496 [Abstract] [Full Text]  
• Zhao, L.-J., Zhang, X.-L., Zhao, P., Cao, J., Cao, M.-M., Zhu, S.-Y., Liu, H.-Q., Qi, Z.-T. (2006). Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line. J. Leukoc. Biol. 80: 424-432 [Abstract] [Full Text]  
• Brzozka, K., Finke, S., Conzelmann, K.-K. (2006). Inhibition of Interferon Signaling by Rabies Virus Phosphoprotein P: Activation-Dependent Binding of STAT1 and STAT2. J. Virol. 80: 2675-2683 [Abstract] [Full Text]  
• Wang, Z. W., Sarmento, L., Wang, Y., Li, X.-q., Dhingra, V., Tseggai, T., Jiang, B., Fu, Z. F. (2005). Attenuated Rabies Virus Activates, while Pathogenic Rabies Virus Evades, the Host Innate Immune Responses in the Central Nervous System. J. Virol. 79: 12554-12565 [Abstract] [Full Text]  
• Nakamichi, K., Saiki, M., Sawada, M., Takayama-Ito, M., Yamamuro, Y., Morimoto, K., Kurane, I. (2005). Rabies Virus-Induced Activation of Mitogen-Activated Protein Kinase and NF-{kappa}B Signaling Pathways Regulates Expression of CXC and CC Chemokine Ligands in Microglia. J. Virol. 79: 11801-11812 [Abstract] [Full Text]