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.
Highlights
The innate immune response, known as one of key mechanisms of host defense, can eliminate tumor cells during the early stages of tumor formation, and is required for the maintenance and renewal of tumor-specific T cell immunity
Jarahian et al found that direct activattion of natural killer (NK) cells by Hemagglutininneuraminidase (HN), the viral envelope protein of Newcastle disease virus (NDV),contributes to the antitumor effects of NDV and HN serves as a ligand structure for the natural cytotoxicity receptors NKp44 and NKp46, which are killer activation receptors (KARs) in human NK cells [25].We hypothesized that these interactions between HN and KARs may be as one of IFN-γ-independent signaling mechanisms that mediated the upregulation of TNF-related apoptosis-inducing ligand (TRAIL) in NDV-induced NK cells
Exposure of NK cells to NDV induces antitumor effects that is partly mediated by the upregulation of TRAIL effectors, via an IFN-γ-dependent pathway [18].To evaluate the upregulated expression of TRAIL exists without the participation of IFN-γ, we investigated whether stimulation with NDV resulted in an increase in TRAIL+ NK cells in IFN-R1-/- mice, and compared TRAIL expression levels between IFN-R1+/+ and IFN-R1-/- mice
Summary
The innate immune response, known as one of key mechanisms of host defense, can eliminate tumor cells during the early stages of tumor formation, and is required for the maintenance and renewal of tumor-specific T cell immunity. NDV stimulates innate antitumor immune responses by enhancing the cytotoxic functions and cytokine production of dendritic cells (DCs), natural killer (NK) cells, and macrophages [16,17,18,19]. Jarahian et al found that direct activattion of NK cells by Hemagglutininneuraminidase (HN), the viral envelope protein of NDV,contributes to the antitumor effects of NDV and HN serves as a ligand structure for the natural cytotoxicity receptors NKp44 and NKp46, which are killer activation receptors (KARs) in human NK cells [25].We hypothesized that these interactions between HN and KARs may be as one of IFN-γ-independent signaling mechanisms that mediated the upregulation of TRAIL in NDV-induced NK cells. We attempted to show that KARs play an important role during the early stages of the innate immune response against tumor cells
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