TRAIL is Involved in the Tumoricidal Activity of Mouse Natural Killer Cells Stimulated by Newcastle Disease Virus <i>in Vitro</i>

Song

Liang³

et al. 2017

PLoS ONE

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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.

Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Song

Liang³

et al. 2017

PLoS ONE

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“…More recently, the NDV strain 7793 was used to active murine NK cells. NDV 7793-activated NK cells overexpressed TRAIL in membrane and in supernatants respect to untreated cells, and the effect was similar to that of IFN-γ-activated NK cells (48). According to our study, human PBMC stimulated with the rNDV increased significantly the levels of TRAIL secreted into the culture supernatants, as well as the mRNA expression.…”

Section: Discussionsupporting

confidence: 76%

Antitumor and immunostimulatory activities of a genotype V recombinant attenuated veterinary Newcastle disease virus vaccine

et al. 2017

Abstract. Antitumor conventional treatments including chemo/radiotherapy result in several side effects and non-specificity. Therapies including the use of oncolytic viruses, particularly the Newcastle disease virus (NDV), have emerged as an attractive alternative due to their capacity to kill cancer cells directly or through stimulation of the immune system. In the present study, a commercial vaccine composed of a recombinant attenuated NDV strain P05 (rNDV-P05) was assessed for antitumor and immunostimulatory activity. Firstly, hemagglutination activity was evaluated at different pH and temperature conditions. Then, cancer cell lines and peripheral blood mononuclear cells (PBMC) were co-cultured with or without rNDV-P05 and cytoplasmic nucleosomes were measured by enzyme-linked immunosorbent assay (ELISA) as an apoptosis indicator. Antitumor cytokines produced by PBMC in response to the virus were analyzed by ELISA and reverse transcription quantitative polymerase chain reaction. Characterization of rNDV-P05 indicates that the virus is slightly sensible to acid and basic pH, and stable at temperatures no greater than 42˚C. The majority of cell lines developed apoptosis in co-culture with rNDV-P05 in a dose-time dependent manner. The highest level of HeLa, HCC1954 and HepG2 cell apoptosis was at 48 h/50 hemagglutination units (HU), and HL-60 was 24 h/50 HU. A549 cell line and PBMC did not show sensitivity to apoptosis by the virus. PBMC from healthy donors stimulated with the rNDV-P05 increased significantly the levels of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α and soluble TNF-related apoptosis-inducing ligand in culture supernatants, as well as their mRNA expression. These results demonstrate that the pro-apoptotic effect of rNDV-P05 and its magnitude is specific to particular tumor cell lines and is not induced on PBMC; and the virus stimulates the expression of several key antitumor cytokines. This study promotes the use of rNDV-P05 in an alternate application of different viral strains during virotherapy with NDV.

Killing Effects of IFN R^−/− Mouse NK Cells Activated by HN Protein of NDV on Mouse Hepatoma Cells and Possible Mechanism with Syk and NF‐κB

Lin

et al. 2019

The Anatomical Record

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The objective of this article is to evaluate whether the tumoricidal activity of mouse IFN R−/− nature killer (NK) cells is induced by Newcastle disease virus hemagglutinin‐neuraminidase (NDV‐HN) stimulation, and to investigate what is the mechanism of the HN‐stimulated NK cells to kill mouse hepatoma cell line in vitro. The mouse IFN R−/− NK cells were stimulated for 16 hr with 500 ng/mL NDV‐HN in 1640 medium. Quantify the cytotoxic activities of NK cells against mouse hepatoma cells (Hepa1‐6) by flow cytometry. Granzymes B (GrB) and Fas/FasL concentrations in the supernatants of IFN R−/− NK cells medium were determined by specific ELISA assay. The expression of cell surface GrB and Fas was determined by Western blot. NDV‐HN stimulation enhanced tumoricidal activity of IFN R−/− NK cells toward Hepa1‐6 in vitro. Treating with anti‐HN neutralizing mAb induced significant decline in the cytotoxicity of IFN R−/− NK cells toward Hepa1‐6 cell line (P < 0.05). After treating with anti‐HN protein (1 μL/mL), Syk‐specific inhibitor Herbimycin A(250 ng/mL) and NF‐κB inhibitor PDTC (500 ng/mL) downregulated the tumoricidal activity of HN‐stimulated IFN R−/− NK cells (P < 0.05). Moreover, significant suppressions in the production of GrB and Fas/FasL were observed in HN‐stimulated IFN R−/− NK cells (P < 0.05). Thus, we concluded that killer activation receptors pathway is involved in the IFN‐γ‐independent GrB and Fas/FasL expression of NDV‐HN‐stimulated IFN R−/− NK cells, and these are activated by Syk and NF‐κB. Anat Rec, 302:1718–1725, 2019. © 2019 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association for Anatomy