This study investigates the role of type I IL-1 receptor (IL-1R1) in mediating the recruitment of leukocytes into the brain parenchyma in mice. Intracerebroventricular (icv) injection of interleukin IL-1beta induced infiltration of leukocytes between 8 and 72 h after the injection. Leukocytes were rarely found in the brain tissue of saline-injected animals. At 8h after IL-1beta injection, leukocytes were seen lining the blood vessels of the brain and sparsely scattered infiltration of leukocytes was found in the cortex. Peak infiltration of leukocytes, which distributed evenly throughout the brain, was seen at 16 h post-injection. The number of leukocytes in the brain declined thereafter and no leukocytes were found 72 h post-injection. This phenomenon was replicated in mice deficient in lymphotoxin-alpha (LT(alpha)), IL-6, interferon (IFN)-gamma receptor, or the tumor necrosis factor (TNF)-alpha receptor, but abrogated in animals deficient in IL-1R1. ICV injection of IFN-gamma or TNF-alpha, but not IL-6 or IL-12, also induced leukocyte infiltration into the brain. Injection of IL-1beta, IFN-gamma, TNF-alpha, IL-6, and IL-12 induced IL-1beta expression in the brain, with IL-6 and IL-12 being the least effective. Leukocyte infiltration induced by icv IFN-gamma and TNF-alpha was also abrogated in IL-1R1-knockout animals. The induced infiltrating leukocytes were identified as neutrophils. Chronic infection with Trypanosoma brucei resulted in the recruitment of T cells, but no other cell types, into the brain. This did not occur in IL-1R1-knockout mice. Thus, IL-1R1 appears to be important for the recruitment of leukocytes across the blood-brain barrier.