The hemagglutinin-neuramidinase protein of Newcastle disease virus upregulates expression of the TRAIL gene in murine natural killer cells through the activation of Syk and NF-κB.

Abstract

Newcastle disease virus (NDV) is responsible for tumoricidal activity in vitro and in vivo. However, the mechanisms that lead to this activity are unclear. Natural killer cells are able to induce apoptosis of tumor cells through multiple pathways, including the tumor necrosis factor-related apoptosis-inducing ligand-death receptor pathway. We previously showed that exposure of NK and T cells to NDV resulted in enhanced tumoricidal activity that was mediated by upregulated expression of the TRAIL gene, via an interferon gamma -dependent pathway. Other pathways involved in the upregulated expression of TRAIL are yet to be identified. In the current study, we used mice in which the IFN-γ receptor one gene was inactivated functionally. We identified an IFN-γ-independent TRAIL pathway in the NDV-stimulated NK cells. Hemagglutinin-neuramidinase induced expression of the TRAIL gene in IFN-R1-/- NK cells by binding to the NKp46 receptor. This upregulation was inhibited by pretreatment of NDV with a neutralizing monoclonal antibody against HN, or desialylation of NK cells. Phosphorylation of spleen tryosine kinases and IκBα was increased in HN-induced IFN-R1-/- NK cells. Treatment with the HN neutralizing monoclonal antibody, pharmacological disialylation, or a Syk inhibitor decreased Syk and IκBα phosphorylation levels. We concluded that killer activation receptors pathway is involved in the IFN-γ-independent TRAIL expression of NDV-stimulated NK cells, and these are activated by Syk and NF-κB.