Inhibition of γ-Secretase Cleavage in the Notch Signaling Pathway Blocks HSV-2-Induced Type I and Type II Interferon Production

We have evaluated the role of gamma-secretase, which is a crucial component in the Notch-induced signaling cascade, on herpes simplex virus type 2 (HSV-2)-induced innate and acquired interferon responses in human CD4(+) T cells and plasmacytoid dendritic cells (pDC). We found that blockade of the Notch signaling pathway with a pharmacological gamma-secretase inhibitor blocked both HSV-2-induced interferon-gamma (IFN-gamma) production in CD4(+) T cells, and HSV-2-induced IFN-alpha production in pDC in a dose-dependent fashion. These effects were not due to an overall suppressive capacity of the g-secretase inhibitor, as it affected neither phytohemagglutinin (PHA)induced IFN-gamma production in CD4(+) T cells, nor CpG-induced IFN-alpha production in pDC. Our data suggest that Notch signaling could be involved in HSV-2-induced interferon responses in CD4(+) T-cells and pDC.