Human type I IFNs directly induces autophagy. We report for the first time that human type I IFNs directly induce autophagy in a dose- and time-dependent manner in Daudi cells,as indicated by the up-regulation of key autophagy dependent markers (LC3-II, Atg5/12 complex and p62)and the formation of autophagosomal structures as visualized by transmission electron microscopy. The induction of autophagy correlates with type I IFN antiproliferative activity in Daudi cells. The induction of autophagy by Type I IFN correlates with the inactivation of the mTOR and MAPK pathways.Treatment of Daudi cells with type I IFNs correlates with the inactivation of the mTOR pathway as demonstrated by the decrease in phosphorylation of proteins downstream of mTOR: p70S6K, S6, 4EBP1 and eIF4B. Combinatory treatment of Daudi cells with the mTOR inhibitor rapamycin and IFN-alpha2c increased the level of LC3-II indicating that the PI3K/AKT/mTORC1 signaling pathway may affect IFN-induced autophagy in Daudi cells. To strengthen evidence that induction of autophagy is a direct result of IFN treatment, Daudi cells were cultured in the presence or absence of anti-IFNAR2-mAb A10, in media from mock treated Daudi cells or cells treated with IFN-alpha 2c for 24 h. An increase of LC3-II was only observed in cells cultured in media containing IFN-alpha2c. Thus, our findings confirmed that autophagy is the direct result of Type I IFN treatment.
|Schmeisser, Hana; Fey, Samuel B; Horowitz, Julie et al. (2013) Type I interferons induce autophagy in certain human cancer cell lines. Autophagy 9:683-96|