Abstract
Peripherally administered cytokines profoundly affect the central nervous system (CNS). One mechanism by which they could affect the CNS is by crossing the blood-brain barrier (BBB) to interact directly with brain receptors. Human and murine IL-1α (hIL-1α; mIL-1α) are transported across the murine BBB with a high rate of transport into the posterior division of the septum (PDS), but it is unknown whether BBB transport is relevant to their actions. Here, we injected species-specific blocking antibodies into the PDS to determine whether transport across the BBB is required for blood-borne hIL-1α to affect memory. Retention was impaired in a dose-dependent manner when hIL-1α was injected either by tail vein (i.v.) or into the PDS, with the PDS route being 1000 times more potent. About 70% of the memory impairment induced by i.v. hIL-1α was reversed by injecting a blocking antibody (Ab) specific for hIL-1α into the PDS. This shows that much of the memory impairment induced by hIL-1α depends on its ability to cross the BBB. Ab specific for mIL-1α was also effective in reversing memory impairment, showing that hIL-1α releases mIL-1α from endogenous stores. Whether the mIL-1α was released from peripheral stores, which would require it to cross the BBB, or from brain stores is unknown. In conclusion, these results show that exogenous, blood-borne hIL-1α affects memory by releasing mIL-1α from endogenous stores and by crossing the BBB to act at sites within the PDS.
Footnotes
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This study was supported by Veterans Affairs Merit review, R01 AA12743, and R01 NS41863.
- Abbreviations:
- CNS
- central nervous system
- IL-1
- interleukin-1
- BBB
- blood-brain barrier
- hIL-1α
- human interleukin-1α
- mIL-1α
- murine interleukin-1α
- mIL-1β
- murine interleukin-1β
- PDS
- posterior division of the septum
- hIL-1β
- human interleukin-1β
- Ab
- antibody
- GS
- goat serum
- Ab-h1α
- blocking antibody specific for human IL-1α
- Ab-h1β
- blocking antibody specific for human IL-1β
- Ab-m1α
- blocking antibody specific for murine IL-1α
- Ab-m1β
- blocking antibody specific for murine IL-1β
- ND50
- concentration of antibody required to yield one-half-maximal inhibition of the [3H]thymidine incorporation by murine T-helper D10.G4.1 cells when the cytokine is present at a concentration just high enough to elicit a maximum response
- I-hIL-1β
- hIL-1β radioactively labeled with131I
- Ki
- unidirectional influx rate
- ANOVA
- analysis of variance
- NS
- normal saline
- CSF
- cerebrospinal fluid
- Received June 22, 2001.
- Accepted August 3, 2001.
- U.S. Government
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