Interleukin-1-induced neurotoxicity is mediated by glia and requires caspase activation and free radical release


Address correspondence and reprint requests to Nancy J. Rothwell, Faculty of Life Sciences, Michael Smith Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK.


Interleukin (IL)-1 expression is induced rapidly in response to diverse CNS insults and is a key mediator of experimentally induced neuronal injury. However, the mechanisms of IL-1-induced neurotoxicity are unknown. The aim of the present study was to examine the toxic effects of IL-1 on rat cortical cell cultures. Treatment with IL-1β did not affect the viability of pure cortical neurones. However, IL-1 treatment of cocultures of neurones with glia or purified astrocytes induced caspase activation resulting in neuronal death. Neuronal cell death induced by IL-1 was prevented by pre-treatment with the IL-1 receptor antagonist, the broad spectrum caspase inhibitor Boc-Asp-(OMe)-CH2F or the antioxidant α-tocopherol. The NMDA receptor antagonist dizolcipine (MK-801) attenuated cell death induced by low doses of IL-1β but the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) had no effect. Inhibition of inducible nitric oxide synthase with N(ω)-nitro-l-arginine methyl ester had no effect on neuronal cell death induced by IL-1β. Thus, IL-1 activates the IL-1 type 1 receptor in astrocytes to induce caspase-dependent neuronal death, which is dependent on the release of free radicals and may contribute to neuronal cell death in CNS diseases.