Saturable entry of leukemia inhibitory factor from blood to the central nervous system

Leukemia inhibitory factor (LIF) is a neurotrophic cytokine now under clinical investigation for its effects on the CNS. We studied its passage across the blood-brain barrier (BBB) from blood to brain and spinal cord. Although a large amount of LIF was reversibly associated with the cerebral vasculature, intact LIF did reach brain parenchyma. Multiple-time regression analysis showed ready access of LIF to the CNS at a rate much faster than that of the vascular marker albumin. Excess LIF inhibited the entry of 125I-LIF after administration i.v. or by in-situ perfusion in blood-free buffer. Efflux of LIF from brain to blood was slower than reabsorption by CSF bulk flow, indicating that LIF tended to be retained in the brain. Although ciliary neurotrophic factor (CNTF) and LIF bind to the same receptor complex, CNTF did not cross-inhibit the entry of LIF into the CNS. A monoclonal antibody to LIF, however, abolished the entry of LIF. Our results show that peripherally administered LIF readily enters the brain and spinal cord by a saturable transport system across the BBB that may have biological implications.