@article{3087011,
    title = "Cell-autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress",
    author = "Mihailidou, C. and Papavassiliou, A.G. and Kiaris, H.",
    journal = "The FASEB Journal",
    year = "2017",
    volume = "31",
    number = "12",
    pages = "5432-5439",
    publisher = "Federation of American Society of Experimental Biology (FASEB)",
    issn = "0892-6638, 1530-6860",
    doi = "10.1096/fj.201700152R",
    keywords = "4 phenylbutyric acid;  azacitidine;  caspase;  CCAAT enhancer binding protein;  ciclopirox;  interferon;  interferon receptor;  tauroursodeoxycholic acid;  transcription factor;  4-phenylbutyric acid;  arylbutyric acid derivative;  azacitidine;  interferon;  pyridone derivative;  taurochenodeoxycholic acid, animal cell;  Article;  cell activity;  cell death;  controlled study;  cytotoxicity;  endoplasmic reticulum stress;  enzyme activation;  fibroblast;  interferon production;  mouse;  nonhuman;  priority journal;  protein expression;  protein misfolding;  unfolded protein response;  animal;  C57BL mouse;  cell culture;  cell survival;  drug effects;  endoplasmic reticulum stress;  enzyme linked immunosorbent assay;  metabolism;  Western blotting, Animals;  Azacitidine;  Blotting, Western;  Cell Death;  Cell Survival;  Cells, Cultured;  Endoplasmic Reticulum Stress;  Enzyme-Linked Immunosorbent Assay;  Interferon Type I;  Mice;  Mice, Inbred C57BL;  Phenylbutyrates;  Pyridones;  Taurochenodeoxycholic Acid;  Unfolded Protein Response",
    abstract = "The interaction of IFN with specific membrane receptors that transduce death-inducing signals is considered to be the principle mechanism of IFN-induced cytotoxicity. In this study, the classic non–cell-autonomous cytotoxicity of IFN was augmented by cell-autonomous mechanisms that operated independently of the interaction of IFN with its receptors. Cells primed to produce IFN by 5-azacytidine (5-aza) underwent endoplasmic reticulum (ER) stress. The chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylbutyrate (4-PBA), as well as the iron chelator ciclopirox (CPX), which reduces ER stress, alleviated the cytotoxicity of 5-aza. Ablation of CCAAT-enhancer-binding protein homologous protein (CHOP), the major ER stress–associated proapoptotic transcription factor, protected fibroblasts from 5-aza only when the cytotoxicity was examined cell autonomously. In a medium-transfer experiment in which the cell-autonomous effects of 5-aza was dissociated, CHOP ablation was incapable of modulating cytotoxicity; however, neutralization of IFN receptor was highly effective. Also the levels of caspase activation showed a distinct profile between the cell-autonomous and the medium-transfer experiments. We suggest that besides the classic paracrine mechanism, cell-autonomous mechanisms that involve induction of ER stress also participate. These results have implications in the development of anti-IFN-based therapies and expand the class of pathologic states that are viewed as protein-misfolding diseases."
}