Multiple signalling pathways interact in the regulation of nerve growth factor production in L929 fibroblasts

Fibroblasts are one of several cell types producing nerve growth factor (NGF) in neuronal targets. In previous studies we found that NGF production is up-regulated by 12-O-tetradecanoylphorbol 13-acetate (TPA) and serum, down-regulated by corticosterone, and unaffected by dibutyryl-cyclic AMP (db-cyclic AMP) in fibroblasts. As fibroblasts in vivo are likely to be exposed to regulatory effects by more than one of these agents at any given time, we examined the effects of combinations of them on NGF production using L929 fibroblasts as a model system. TPA and serum together stimulated NGF production 10-fold more than either agent alone. Corticosterone reduced NGF mRNA and NGF production to less than 10% of basal levels whether or not TPA or serum, or both, were present but not in the presence of the glucocorticoid antagonist RU486. Corticosterone did not increase the rate of NGF mRNA degradation. Forskolin and db-cyclic AMP prevented NGF mRNA induction by TPA and serum without changing basal levels. TPA induced c-fos and junB mRNAs transiently and preceding NGF mRNA induction but c-jun mRNA remained undetectable. Forskolin enhanced the induction of both junB and c-fos mRNA whereas corticosterone prolonged junB mRNA induction. Thus, TPA induction of NGF mRNA is modulated differentially by corticosterone and cyclic AMP. c-fos and junB may play a role in the underlying mechanisms.