Abstract
Airway epithelial cells are the first line of defense against viral infections and are instrumental in coordinating the inflammatory response. In this study, we demonstrate the synergistic stimulation of CXCL10 mRNA and protein, a key chemokine responsible for the early immune response to viral infection, following treatment of airway epithelial cells with IFN γ and influenza virus. The synergism also occurred when the cells were treated with IFN γ and a viral replication mimicker (dsRNA) both in vitro and in vivo. Despite the requirement of type I interferon (IFNAR) signaling in dsRNA-induced CXCL10, the synergism was independent of the IFNAR pathway since it wasn’t affected by the addition of a neutralizing IFNAR antibody or the complete lack of IFNAR expression. Furthermore, the same synergistic effect was also observed when a CXCL10 promoter reporter was examined. Although the responsive promoter region contains both ISRE and NFκB sites, western blot analysis indicated that the combined treatment of IFN γ and dsRNA significantly augmented NFκB but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN γ and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NFκB-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.
Highlights
Influenza pneumonia remains a major cause of morbidity and mortality worldwide
These results demonstrate that influenza virus in combination with IFN c synergistically induce CXCL10 mRNA and protein production from primary human airway epithelial cells
This is the first report documenting the observation and mechanism underlying the synergism between IFN c and viral infection in airway epithelial cells
Summary
Influenza pneumonia remains a major cause of morbidity and mortality worldwide. Airway epithelial cells are the first line of defense against viral infections in the lung and are instrumental in coordinating the early inflammation leading to an adaptive immune response. The role of CXCL10 in viral pneumonia has not been thoroughly characterized but evidence suggests it is important for the migration of NK cells, macrophages, T cells, neutrophils and plasmacytoid dendritic cells into the lung [3,4]. Synergistic induction of CXCL10 has been described with IFN c in conjunction with HIV-1 in human astrocytes and macrophages and thought to play a role in HIV induced encephalopathy [14,15]. This marked variety of pro-inflammatory molecules that elicit a synergistic response of CXCL10 in a wide variety of cell types is indicative of a highly conserved and likely biologically important cellular response. Synergistic induction of CXCL10 in response to influenza and IFN c in airway epithelial cells has not been previously reported
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