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Journal of Virology, August 2006, p. 8248-8258, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00162-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Rhinovirus Replication in Human Macrophages Induces NF-{kappa}B-Dependent Tumor Necrosis Factor Alpha Production

Vasile Laza-Stanca,1 Luminita A. Stanciu,1 Simon D. Message,1 Michael R. Edwards,1 James E. Gern,2 and Sebastian L. Johnston1*

Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, London, United Kingdom,1 Department of Pediatrics, University of Wisconsin—Madison, Madison, Wisconsin2

Received 24 January 2006/ Accepted 12 May 2006

Rhinoviruses (RV) are the major cause of acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Rhinoviruses have been shown to activate macrophages, but rhinovirus replication in macrophages has not been reported. Tumor necrosis factor alpha (TNF-{alpha}) is implicated in the pathogenesis of acute exacerbations, but its cellular source and mechanisms of induction by virus infection are unclear. We hypothesized that rhinovirus replication in human macrophages causes activation and nuclear translocation of NF-{kappa}B, leading to TNF-{alpha} production. Using macrophages derived from the human monocytic cell line THP-1 and from primary human monocytes, we demonstrated that rhinovirus replication was productive in THP-1 macrophages, leading to release of infectious virus into supernatants, but was limited in monocyte-derived macrophages, likely due to type I interferon production, which was robust in monocyte-derived but deficient in THP-1-derived macrophages. Similar to bronchial epithelial cells, only small numbers of cells supported complete virus replication. We demonstrated RV-induced activation of NF-{kappa}B and colocalization of p65/NF-{kappa}B nuclear translocation with virus replication in both macrophage types. The infection induced TNF-{alpha} release in a time- and dose-dependent, RV serotype- and receptor-independent manner and was largely (THP-1 derived) or completely (monocyte derived) dependent upon virus replication. Finally, we established the requirement for NF-{kappa}B but not p38 mitogen-activated protein kinase in induction of TNF-{alpha}. These data suggest RV infection of macrophages may be an important source of proinflammatory cytokines implicated in the pathogenesis of exacerbations of asthma and COPD. They also confirm inhibition of NF-{kappa}B as a promising target for development of new therapeutic intervention strategies.

* Corresponding author. Mailing address: Department of Respiratory Medicine, National Heart and Lung Institute and Wright Fleming Institute of Infection and Immunity, Imperial College London, Norfolk Place, London W2 1PG, United Kingdom. Phone: 44 20 7594 3764. Fax: 44 20 7262 8913. E-mail: s.johnston{at}imperial.ac.uk.

Journal of Virology, August 2006, p. 8248-8258, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00162-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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