IFN-γ Induces IL-15 Trans-Presentation by Epithelial Cells via IRF1

IL-15 exhibits pleiotropic effects on NK and CD8(+) T cells and contributes to host protection or immunopathology during infection. Although both type I IFNs and IFN-gamma upregulate IL-15 expression, their effects on IL-15 upregulation and underlying mechanisms have not been compared comprehensively. In addition, little is known about trans-presentation of IL-15 by epithelial cells to lymphocytes. In this study, we analyzed the expression of IL-15 and IL-15R alpha in the human hepatocyte-derived Huh-7 cell line after stimulation with IFN-alpha, IFN-beta, or IFN-gamma using RT-PCR, flow cytometry, and confocal microscopy. We also performed knockdown experiments to investigate the signaling pathway involved in IL-15 upregulation. IFN-gamma more potently upregulated IL-15 expression in Huh-7 cells than IFN-alpha and IFN-beta. Knockdown experiments revealed that IFN-gamma- and IFN-beta-induced IL-15 expression relied on IFN regulatory factor 1 (IRF1), which is upregulated by STAT1 and IFN-stimulated gene factor 3, respectively. Inhibitor of kappa B kinase alpha/beta was also involved in IFN-gamma-induced upregulation of IL-15. Furthermore, human NK cells were activated by coculture with IFN-gamma-treated Huh-7 cells, which was abrogated by knocking down IL-15R alpha in IFN-gamma-treated Huh-7 cells, indicating that IFN-gamma-induced IL-15 on Huh-7 cells activates NK cells via trans-presentation. In summary, our data demonstrate that IFN-gamma potently elicits IL-15 trans-presentation by epithelial cells via IRF1. These data also suggest that the IFN gamma-IRF1-IL-15 axis may be a regulatory target for the treatment of diseases with IL-15 dysregulation.