Cytokines such as interleukin-1, which are found in the brain after trauma, regulate expression of nerve growth factor (NGF) mRNA and protein in hippocampal cultures. We have investigated possible mechanisms by which 11-1p regulates NGF in hippocampal cells. The induction of NGF mRNA by 11-1p was blocked by a receptor antagonist indicating that this effect is receptor mediated. II-lp elicited a dramatic induction of c-fos mRNA and a slight elevation of c-jun mRNA in a time dependent manner which may allow for a role in the induction of NGF mRNA expression. We examined whether specific second messenger pathways were involved in mediating the action of 11-1p in the hippocampus. Activation of cAMP with forskolin or treatment with 8-Br-CAMP had no effect on NGF mRNA levels. Moreover, exposure of hippocampal cultures to II-lP evoked no change in cAMP levels, indicating that this second messenger system played little or no role in the regulation of NGF expression by II-lp in these cells. Further, interleukin-1 elicited no change in membrane inositol phosphate turnover, nor did it affect intracellular calcium levels. Treatment of cell cultures with the phorbol ester PMA elicited an increase in NGF mRNA, suggesting that activation of protein kinase C (PKC) may mediate NGF mRNA expression. However, prolonged treatment of cultures with PMA to desensitize PKC did not eliminate the 11-1p induction of NGF mRNA. 11-lp, therefore, did not appear to activate NGF expression via CAMP, Ca2+, or a PKC isoform that is downregulated by prolonged PMA treatment. However, a phosphorylation event may be involved in the signal transduction mechanism, as treatment with okadaic acid to inhibit protein phosphatase 2a potentiated the induction of NGF mRNA by 11-lp. The results presented indicate that 11-1p acts via its receptor to induce a rise in NGF expression. Identification of the specific second messenger pathway has remained elusive; however, a phosphorylation event appears to be intermediary. Moreover, the induction of c-fos and c-jun may represent a final common path in activation of NGF gene expression by different signals such as 11-1p and PMA.