Induction of autophagy and interleukin 6 secretion in bystander cells: metabolic cooperation for radiation-induced rescue effect?

We hypothesized that radiation-induced rescue effect (RIRE) shared similar mechanisms with ‘metabolic cooperation’, in which nutrient-deprived cancer cells prompted normal cells to provide nutrients. Our data demonstrated that X-ray irradiation induced autophagy in HeLa cells, which could last at least 18 h, and proved that the irradiated cells (IRCs) resorted to breaking down their own intracellular components to supply the molecules required for cell-repair enhancement (e.g. to activate the NF-κB pathway) in the absence of support from bystander unirradiated cells (UICs). Furthermore, autophagy accumulation in IRCs was significantly reduced when they were partnered with UICs, and more so with UICs with pre-induced autophagy before partnering (through starvation using Earle’s Balanced Salt Solution), which showed that the autophagy induced in UICs supported the IRCs. Our results also showed that interleukin 6 (IL-6) was secreted by bystander UICs, particularly the UICs with pre-induced autophagy, when they were cultured in the medium having previously conditioned irradiated HeLa cells. It was established that autophagy could activate the signal transducer and activator of transcription 3 (STAT3) that was required for the IL-6 production in the autophagy process. Taken together, the metabolic cooperation of RIRE was likely initiated by the bystander factors released from IRCs, which induced autophagy and activated STAT3 to produce IL-6 in bystander UICs, and was finally manifested in the activation of the NF-κB pathway in IRCs by the IL-6 secreted by the UICs.