INTERLEUKIN-1-BETA ATTENUATES EXCITATORY AMINO ACID-INDUCED NEURODEGENERATION IN-VITRO - INVOLVEMENT OF NERVE GROWTH-FACTOR

Certain cytokines have been reported to exert neurotrophic actions in vivo and in vitro, In the present study, we investigated the possible neuroprotective actions of the cytokine human recombinant interleukin- 1 beta (hrlL-1 beta) against excitatory amino acid (EAA)-induced neuro degeneration in cultured primary cortical neurons, Brief (15 min) expo sure of cultures to submaximal concentrations of glutamate, NMDA, AMPA , or kainate caused extensive neuronal death (similar to 70% of all ne urons). Neuronal damage induced by the EAAs was significantly reduced (up to 70%) by pretreatment with 500 ng/ml (6.5 x 10(3) U/ml) hrlL-1 b eta for 24 hr, The neuroprotective effect of hrlL-1 beta was reversed by coapplication of an IL-l receptor antagonist (IL-1ra, 50 mu g/ml). Neuroprotective actions of hrlL-1 beta were also reduced by administra tion of a neutralizing monoclonal antibody to NGF (65% inhibition), In concordance, the neurotoxic actions of EAAs were significantly reduce d (by 40%) after pretreatment with NGF (100 ng/ml for 48 hr), Furtherm ore, an additive neuroprotective effect of approximately 75% was obser ved when cultures were exposed to a combination of hrlL-1 beta and NGF , In contrast, exposure of cultures to high concentrations hrlL-1 beta alone (100 mu g/ml, 1.3 x 10(6) U/ml) for periods up to 72 hr resulte d in neurotoxicity, which was reversed by IL-1ra (1 mg/ml). These find ings suggest that hrlL-1 beta can limit EAA-induced neuronal damage. T hese effects appear to be may be mediated, at least in part, via NGF, These findings may be relevant to the understanding of neurodegenerati ve diseases.