Cell‐autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress

• Published in: The FASEB journal 2017-12, Vol.31 (12), p.5432-5439
• Main Authors: Mihailidou, Chrysovalantou, Papavassiliou, Athanasios G., Kiaris, Hippokratis
• Format: Article
• Language: English
• Subjects: 4‐phenylbutyrate; Ablation; Animals; Apoptosis; Azacitidine - pharmacology; Azacytidine; Blotting, Western; Caspase; CCAAT/enhancer-binding protein; Cell Death - drug effects; Cell Survival - drug effects; Cells, Cultured; cellullar death; Chaperones; Ciclopirox; Cytotoxicity; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Enzyme-Linked Immunosorbent Assay; Fibroblasts; Homology; Interferon; Interferon Type I - metabolism; Iron; Mice; Mice, Inbred C57BL; Neutralization; Paracrine signalling; Phenylbutyrates - pharmacology; Phenylbutyric acid; Protein folding; Proteins; Pyridones - pharmacology; Receptors; Stresses; Taurochenodeoxycholic Acid - pharmacology; tauroursodeoxycholate; Toxicity; unfolded protein response; Unfolded Protein Response - drug effects
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201700152R

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.—Mihailidou, C., Papavassiliou, A. G., Kiaris, H. Cell‐autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress. FASEB J. 31, 5432–5439 (2017). www.fasebj.org