For dendritic cells (DCs) to initiate an immune response, their ability to migrate and to produce interleukin-12 (IL-12) is crucial. It has been previously shown that low-dose radiation (LDR) promoted IL-12 production by DCs, resulting in increased DC activity that contributed to LDR hormesis in the immune system. However, the molecular mechanism of LDR-induced IL-12 production, as well as the effect of LDR on DC migration capacity require further elucidation. Using the JAWSII immortalized mouse dendritic cell line, we showed that in vitro X-ray irradiation (0.2 Gy) of DCs significantly increased DC migration and IL-12 production, and upregulated CCR7. The neutralizing antibody against CCR7 has been shown to abolish LDR-enhanced DC migration, demonstrating that CCR7 mediates LDR-promoting DC migration. We identified nuclear factor kappaB (NF-κB) as the central signaling pathway that mediated LDR-enhanced expression of IL-12 and CCR7 based on findings that 0.2 Gy X-ray irradiation activated NF-κB, showing increased nuclear p65 translocation and NF-κB DNA-binding activity, while an NF-κB inhibitor blocked LDR-enhanced expression of IL-12 and CCR7, as well as DC migration. Finally, we demonstrated that 0.2 Gy X-ray irradiation promoted ATM phosphorylation and reactive oxygen species generation; however, only the ATM inhibitor abolished the LDR-induced NF-κB-mediated expression of IL-12 and CCR7. Altogether, our data show that exposure to LDR resulted in a hormetic effect on DCs regarding CCR7-mediated migration and IL-12 production by activating the ATM/NF-κB pathway.

The unsatisfactory clinical efficacy of dendritic cell (DC)-based cancer vaccines prepared by conventional methods is partly due to their insufficient capacity for migration. Our previous study showed that exposure to low-dose radiation (LDR) at a dose of 0.2 Gy promoted DC migration in vitro. The present study further investigates whether exposure to LDR at a dose of 0.2 Gy during the DC vaccine preparation could increase the antitumor effect of DC vaccines derived from mouse bone marrow. Our results showed that the migratory capacities of DCs were significantly increased after exposure to LDR. Furthermore, exposure to LDR resulted in an increased ability of DCs to induce T-cell proliferation, and the cytotoxic effect of cytotoxic T lymphocytes (CTLs) primed by the DCs exposed to LDR was significantly enhanced. An in vivo study using a mouse transplanted tumor model showed that subcutaneous injections of a DC vaccine exposed to LDR led to an increased mouse survival rate, infiltration of CTLs into tumor tissue, and apoptosis of tumor cells, which were accompanied by significant upregulation of serum interferon γ and interleukin 12. These results indicate that exposing DCs to LDR during the DC vaccine preparation is an effective approach to enhance its antitumor effect.

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