To examine the regulation of nerve growth factor (NGF) gene expression with respect to neural trauma, we examined the effects of T cell-derived lymphokines on NGF synthesis/secretion in cultured mouse astrocytes. Interleukin (IL)-4 and IL-5 significantly increased the amount of NGF secreted by astrocytes, whereas IL-2, IL-3, and IL-6 had no significant effect. IL-4 and IL-5 produced marked increases in NGF mRNA levels in astrocytes as demonstrated by the reverse transcription-polymerase chain reaction (RT-PCR) method. The effect of IL-4 and IL-5 was greater in quiescent astrocytes than in growing cells. Neither increase in thymidine incorporation nor any morphological change was observed during the treatment with IL-4 and IL-5. The stimulatory effect of IL-4 and IL-5 on NGF synthesis was completely inhibited by the addition of anti-IL-4 monoclonal antibody and anti-IL-5 monoclonal antibody, respectively. The results indicate that IL-4 and IL-5 specifically trigger a cascade of events to regulate NGF synthesis in astrocytes, independent of cell growth.