Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jianzhou Chen, Bostjan Markelc, Jakob Kaeppler, Vivian M.L. Ogundipe, Yunhong Cao, W. Gillies McKenna, Ruth J. Muschel
PurposeIonizing radiation augments anti-tumor immune responses with interferons (IFN) acting as mediators. Of the three types of IFNs, type I and II IFNs are induced in irradiated tumors with induction of type III IFNs (IFNLs) currently not reported. Here, we investigated the induction of type III IFNs in human cancer cells by gamma-rays and its mechanisms.Methods and MaterialsType III IFN expression in human cancer cell lines following gamma-ray irradiation in vitro was assessed by RT-qPCR and ELISA. Signaling pathways mediating type III IFN induction were examined by a variety of means, including immunoblotting, flow cytometry, confocal imaging and RT-qPCR. Key mediators in these pathways were further explored and validated using gene CRISPR knockout or shRNA knockdown.ResultsExposure to gamma-rays directly induced type III IFNs (mainly IFNL1) in human cancer cell lines in dose- and time-dependent fashions. The induction of IFNL1 was primarily mediated by the cytosolic DNA sensors-STING-TBK1-IRF1 signaling axis with a lesser contribution from NF-κB signaling in HT29 cells. In addition, type III IFN signaling through its receptors serves as a positive feedback loop further enhancing IFN expression via upregulation of the kinases in the STING-TBK1 signaling axis.ConclusionsOur results suggest that IFNL1 can be upregulated in human cancer cell lines following gamma-rays treatment. In HT29 cells this induction occurs via the STING pathway adding another layer of complexity to the understanding of radiation-induced anti-tumor immunity and may provide novel insights into IFN-based cancer treatment.
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