I.c.v. injection of interleukin-1beta induces infiltration of leukocytes into the brain. I.p. injection of bacterial endotoxin lipopolysaccharide induces the expression of interleukin-1 in the CNS without causing the entry of leukocytes into the brain. This suggests that during systemic inflammation trafficking of potentially damaging leukocytes into the CNS is inhibited. In this study, we investigated the effects of peripheral injection of lipopolysaccharide on brain leukocyte recruitment induced by i.c.v.-interleukin-1 in mice. I.c.v.-interleukin-1 induced widespread infiltration of leukocytes into the brain 16 h after the injection. Pretreatment with i.p.-lipopolysaccharide 2 h before the i.c.v. interleukin-1 injection completely blocked interleukin-1-induced leukocyte infiltration, whereas i.p.-LPS only attenuated the effect of interleukin-1 if it was given 12 h before i.c.v. interleukin-1 injection. I.p.-lipopolysaccharide given 24 h before i.c.v. interleukin-1 injection did not alter interleukin-1 induced leukocyte infiltration. I.c.v.-interleukin-1 induced expression of p- and e-selectins in brain vasculatures prior to the appearance of leukocytes in the brain parenchyma. Induction of p- and e-selectin was inhibited by the pretreatment of i.p.-lipopolysaccharide 2 h, but not 24 h, before i.c.v.-interleukin-1 injection. I.c.v.-interleukin-1-induced leukocyte infiltration was diminished in both e- and p- selectin knockout animals. These results suggest that systemic inflammation actively inhibits recruitment of leukocytes by CNS. Inhibition of the expression of p- and e-selectins is a mechanism by which peripheral inflammation regulate CNS leukocyte recruitment.