Synergistic Up-Regulation of CXCL10 by Virus and IFN γ in Human Airway Epithelial Cells

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 gamma and influenza virus. The synergism also occurred when the cells were treated with IFN gamma 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 NF kappa B sites, western blot analysis indicated that the combined treatment of IFN gamma and dsRNA significantly augmented NF kappa B but not STAT1 activation as compared to the single treatment. Therefore, we conclude that IFN gamma and dsRNA act in concert to potentiate CXCL10 expression in airway epithelial cells via an NF kappa B-dependent but IFNAR-STAT independent pathway and it is at least partly regulated at the transcriptional level.