Τίτλος:
Cell-autonomous cytotoxicity of type I interferon response via induction of endoplasmic reticulum stress
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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.
Συγγραφείς:
Mihailidou, C.
Papavassiliou, A.G.
Kiaris, H.
Περιοδικό:
The FASEB Journal
Εκδότης:
Federation of American Society of Experimental Biology (FASEB)
Λέξεις-κλειδιά:
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
DOI:
10.1096/fj.201700152R
