The central nervous system injury that can result after radiotherapy has been suggested to involve induced gene expression and cytokine production. We have previously shown that irradiation of primary cultures of rat astrocytes results in the activation of NF kappa B. To determine whether such an effect also occurs in vivo, NF kappa B activity was analyzed in the cerebral cortex of the rat brain after whole body irradiation. After a single dose of 15 Gy, NF kappa B activity was increased by 2 h postirradiation, returning to unirradiated levels by 8 hours. The increase was dose-dependent beginning at 2 Gy and continuing to at least 22.5 Gy. NF kappa B activity in the irradiated cortex was not accompanied by I kappa B alpha degradation. When 7.5 Gy was delivered 24 h before the 15 Gy, the increase in NF kappa B activity after 15 Gy was significantly reduced. These results suggest that an initial exposure to radiation induced a refractory period in the brain during which the susceptibility of NF kappa B to activation by subsequent irradiation was significantly reduced. This period of reduced sensitivity to radiation was also apparent for the induction of the NF kappa B-regulated cytokines IL-1 beta, IL-6, and TNF alpha.