title: Permeability of the mouse blood-brain barrier to murine interleukin-2: predominance of a saturable efflux system.
abstract: Interleukin (IL)-2, a T helper (TH)1 cell-derived glycoprotein with potent neuromodulatory effects, is implicated in the etiology and pathogenesis of various psychiatric and neurological disorders. Paralleling these findings, chronic IL-2 intravenous immunotherapy may induce similar psychopathological outcomes. The findings that acute or repeated injections of IL-2 induce motor and cognitive abnormalities in rodents are consistent with these clinical findings, and raise the possibility that IL-2 crosses the blood-brain barrier (BBB) to alter brain function. However, little is known about the ability of IL-2 to enter the brain or whether its effects vary with the chronicity of IL-2 treatment. Here, we found that radioactively labeled mouse IL-2 (I-IL-2) given intravenously entered the brain at a low rate (Ki=0.142+/-0.044microl/g-min) by a non-saturable process. Repeated injections of either IL-2 or vehicle altered the kinetics of entry without producing a net effect on IL-2 entry. When I-IL-2 was given by brain perfusion, the entry rate greatly increased over 10-fold to 2.2+/-0.805microl/g-min. This suggests a circulating factor is retarding the entry of IL-2 into the brain. A paradoxic increase in the rate of I-IL-2 entry into brain occurred when an excess of unlabeled IL-2 was included in the brain perfusate, suggesting a saturable CNS-to-blood efflux system. Intracerebroventricular injection of I-IL-2 with and without unlabeled IL-2 confirmed the presence of a saturable efflux system. We conclude that IL-2 entry into the brain is low because of the absence of a blood-to-brain transporter and further retarded by circulating factors and a CNS-to-blood efflux system. This is the first description of a saturable CNS-to-blood efflux system for a cytokine. We postulate that this efflux system may protect the brain from circulating IL-2.
authors.affiliation: Division of Geriatrics, Department of Internal Medicine, GRECC, Veterans Affairs Medical Center-St. Louis and Saint Louis University School of Medicine, 915 N. Grand Blvd, St. Louis, MO 63106, USA. bankswa@slu.edu
authors.forename: William A
authors.initials: WA
authors.lastname: Banks
authors.forename: Michael L
authors.initials: ML
authors.lastname: Niehoff
authors.forename: Steven S
authors.initials: SS
authors.lastname: Zalcman
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology; D004334:Drug Administration Schedule; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D011897:Random Allocation; D013045:Species Specificity; D014018:Tissue Distribution
chemical_list: D007376:Interleukin-2