In a continuation of our earlier study on the involvement of HSP25 (now known as Hspb1) and HSP70 (now known as Hspa4) in the induction of an adaptive response, we examined the involvement of these proteins in the induction of the adaptive response using an animal model system. C57BL6 mice were irradiated with 5 cGy of gamma radiation three times in 1 week (for a total of 15 cGy), and a high challenge dose (6 Gy) was given on the day after the last low-dose irradiation. The survival time of the low-dose preirradiated mice was increased to 30%. The induction of apoptosis induced by 6 Gy was also reduced by this low-dose preirradiation regimen. To elucidate any link existing between the HSPs and the induction of the adaptive response, reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis was performed using splenocytes. High-dose radiation up-regulated the expression of Hspb1 and especially Hspa4, while expression of other HSPs such as HSC70 (now know as Hspa8), Hsp90, and alphaB-crystalline (now known as Cryab) did not change. When splenocytes from Hspa4 transgenic mice were preirradiated with a low dose of radiation, a reduction in cell death after high-dose irradiation was observed. These results suggest that Hspa4 is a key molecule in the induction of the adaptive response.