Interleukin-18 induces acute biphasic reduction in the levels of circulating leukocytes in mice

We investigated the acute hematological changes caused by interleukin-18 (IL-18) in mice. Intraperitoneal administration of IL-18 (2 mug/mouse) resulted in biphasic decreases in the number of leukocytes in the blood. The first phase of decrease occurred within 2 h of IL-18 administration and was followed by a transient increase at 5 h. The second phase of decrease occurred at around 6 It, reaching a nadir which lasted for more than 24 h. In mice deficient in inducible nitric oxide (NO) synthase, the first phase of reduction of leukocytes did not occur although the second phase of decrease was observed. In mice deficient in gamma interferon (IFN-gamma) or in mice depleted of natural killer cells and incapable of producing IFN-gamma, IL-18 had no effect on the number of circulating leukocytes. Levels of nitrite and/or nitrate in the serum were elevated within 2 h after administration of IL-18, reaching a peak at 4 h and then decreasing gradually to the basal level over a 24-h period of time. On the other hand, serum IFN-gamma levels changed in a biphasic manner, reaching a peak at 2 h after IL-18 administration, followed by a decrease in the basal level and a second increase at 6 h. Levels of IL-18 receptor mRNAs also showed biphasic changes in correlation with the changes in serum IFN-gamma levels. These results suggest that the changes in the leukocyte number following IL-18 administration are mediated by NO and IFN-gamma, with NO being involved in the first phase of reduction and IFN-gamma being involved in both phases.