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 (hrIL-1 beta) against excitatory amino acid (EAA)-induced neurodegeneration in cultured primary cortical neurons. Brief (15 min) exposure of cultures to submaximal concentrations of glutamate, NMDA, AMPA, or kainate caused extensive neuronal death (approximately 70% of all neurons). 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) hrIL-1 beta for 24 hr. The neuroprotective effect of hrIL-1 beta was reversed by coapplication of an IL-1 receptor antagonist (IL-1ra, 50 micrograms/ml). Neuroprotective actions of hrIL-1 beta were also reduced by administration of a neutralizing monoclonal antibody to NGF (65% inhibition). In concordance, the neurotoxic actions of EAAs were significantly reduced (by 40%) after pretreatment with NGF (100 ng/ml for 48 hr). Furthermore, an additive neuroprotective effect of approximately 75% was observed when cultures were exposed to a combination of hrIL-1 beta and NGF. In contrast, exposure of cultures to high concentrations hrIL-1 beta alone (100 micrograms/ml, 1.3 x 10(6) U/ml) for periods up to 72 hr resulted in neurotoxicity, which was reversed by IL-1ra (1 mg/ml). These findings suggest that hrIL-1 beta can limit EAA-induced neuronal damage. These effects appear to be may be mediated, at least in part, via NGF. These findings may be relevant to the understanding of neurodegenerative diseases.