DNA-PKcs is required for activation of innate immunity by immunostimulatory DNA

Bacterial DNA and related synthetic immunostimulatory oligodeoxyribonucleot ides (ISS-ODN) stimulate innate immunity. However, the molecular recognitio n mechanism that initiates signaling in response to bacterial DNA and ISS-O DN has not been identified. Herein, we demonstrate that administration of b acterial DNA and ISS-ODN to mice lacking the catalytic subunit of DNA-PK (D NA-PKcs) and in vitro stimulation of BMDM from these mice result in defecti ve induction of IL-6 and IL-12. Further analysis using BMDM of IKK beta (-/ -) revealed that both DNA-PKcs and IKK beta are essential for normal cytoki ne production in response to ISS-ODN or bacterial DNA. ISS-ODN and bacteria l DNA activate DNA-PK, which in turn contributes to activation of IKK and N F-kappaB. These results reveal a novel role of DNA-PKcs in innate immune re sponses and a link between DNA repair and innate immunity.