A neurotrophic role for interleukin-1 alpha (IL-1 alpha) was investigated in dissociated spinal cord-dorsal root ganglion cultures. Three observations suggested a survival-promoting action for IL-1 alpha in nine-day-old cultures: (1) neutralizing antiserum to murine IL-1 alpha decreased neuronal survival; (2) treatment with IL-1 alpha in electrically blocked cultures increased neuronal survival; and (3) antiserum to the type I IL-1 receptor decreased neuronal survival. Treatment with VIP prevented neuronal cell death associated with the antiserum to IL-1 alpha. In contrast, treatment of one-month-old cultures with IL-1 alpha produced neuronal cell death and neutralizing antiserum to the IL-1 receptor had no effect on neuronal survival in these cultures. These experiments suggested that an IL-1-like substance was necessary for neuronal survival during a specific stage in development and that a relationship between VIP and IL-1 alpha might account in part for the neurotrophic properties of VIP. To test if VIP might be a secretagogue for IL-1, a neuron-free model system was utilized: astroglial cultures derived from cerebral cortex. VIP treatment produced a concentration-dependent (EC50: 50 pM) increase in the amount of IL-1 alpha in the medium and a decrease in cellular IL-1 alpha. Interleukin-1 beta (IL-1 beta) was also increased (EC 50: 1 nM) in the medium by VIP but without depleting IL-1 beta in the cytosol. Semi-quantitative measurements of the IL-1 alpha mRNA after VIP treatment indicated a significant but transient decrease. These data indicate that VIP produced an increase in the secretion of IL-1 alpha while depleting IL-1 alpha mRNA.