Proinflammatory response induced by Newcastle disease virus in tumor and normal cells

Abstract

Purpose: To investigate the specific role of immune responses induced by lentogenic Newcastle disease virus (NDV) for its antitumor effect. Materials and methods: NDV LaSota strain was used to infect the following human cells: non-small cell lung carcinoma (A549), glioblastoma (U87MG and T98G), mammary gland adenocarcinoma (MCF7 and MDA-MB-453), hepatocellular carcinoma (Huh7), transformed embryonic kidney cells (HEK293), primary monocytes, lung fibroblast (HF19), skin fibroblast (NB1RGB) and rat astroglia (RCR-1) at 0.001 multiplicity of infection. NDV-induced cytotoxicity and expression of proinflammatory cytokines were analyzed using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and multiplex enzyme-linked immunosorbent assay, respectively. Results: Tumor cells (A549, U87MG, T98G, Huh7, MDA-MB-453, and MCF7) showed viability of <44%, while normal cell lines HEK293, NB1RGB, and RCR-1 showed 84%, 73%, and 69% viability at 72 hours postinfection, respectively. Proinflammatory cytokine profiling showed that NDV mainly induced the secretion of interferon (IFN)-α, IFN-β, and IFN-λ in tumor cells and only IFN-λ in normal cells. In addition, NDV infection induced the production of interleukin (IL)-6 in most cells. Conclusion: Our findings suggest a new perspective regarding the role of IFN-λ and IL-6 in the mechanism of tumor selectivity and oncolysis of NDV. Keywords: Newcastle disease virus, oncolytic virus, interferons, cytokines IntroductionEvery year, mortality caused by cancer is increasing globally. This calls for novel therapeutic strategies.1 Use of oncolytic viruses represents a class of promising antitumor therapeutic options, primarily through the direct lysing of cancer cells and secondarily through the potential antitumor response induced by inflammation. [2][3][4][5][6] Newcastle disease virus (NDV) is a negative-strand RNA virus from the family Paramyxoviridae. This virus has been reported to be an effective oncolytic agent in vitro and in vivo against many types of solid tumors such as hepatocellular carcinoma, pancreatic adenocarcinoma, melanoma, pleural mesothelioma, colorectal carcinoma, renal carcinoma, glioblastoma and many others, 5,7-13 as well as in clinical studies in patients with glioblastoma multiforme, colorectal carcinoma, non-small cell lung carcinoma, renal carcinoma, breast adenocarcinoma, mesothelioma and pancreatic adenocarcinoma.14-18 NDV causes a disease that predominantly affects poultry, although infection in humans has been reported to cause conjunctivitis 19,20 and/or mild flu-like symptoms. [13][14][15][16][17]21 Based on their virulence on birds, NDV strains can be divided into 23-27 NDV is postulated to be a potent type I IFN inducer, but due to defective IFN signaling in tumor cells NDV replicates better in tumor cells. This has been the basis of tumor selective replication of NDV. 11,18,[28][29][30][31] The evidence for type I IFN production in vitro and in vivo after NDV infection has been obtained by measuring the level of IFN-α/β and the induction...

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