title: Rhinovirus replication in human macrophages induces NF-kappaB-dependent tumor necrosis factor alpha production.
abstract: 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-kappaB, 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-kappaB and colocalization of p65/NF-kappaB 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-kappaB 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-kappaB as a promising target for development of new therapeutic intervention strategies.
authors.affiliation: 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.
authors.forename: Vasile
authors.initials: V
authors.lastname: Laza-Stanca
authors.forename: Luminita A
authors.initials: LA
authors.lastname: Stanciu
authors.forename: Simon D
authors.initials: SD
authors.lastname: Message
authors.forename: Michael R
authors.initials: MR
authors.lastname: Edwards
authors.forename: James E
authors.initials: JE
authors.lastname: Gern
authors.forename: Sebastian L
authors.initials: SL
authors.lastname: Johnston
mesh_terms: D001249:Asthma / Q000276:immunology / Q000821:virology; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000821:virology*; D016328:NF-kappa B / Q000819:agonists / Q000032:analysis / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology / Q000821:virology; D012229:Rhinovirus / Q000502:physiology*; D051996:Transcription Factor RelA / Q000819:agonists / Q000032:analysis / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D016328:NF-kappa B; C439524:TNF protein, human; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha