We have previously shown that after peripheral nerve lesion the synthesis of NGF is induced in cells of the nerve sheath (Heumann et al., 1987a). Further analysis led to the identification of growth factors and intracellular mechanisms responsible for this induction in sciatic fibroblasts (Lindholm et al., 1988; Hengerer et al., 1990). The present work aimed at the elucidation of the regulation of NGF synthesis in Schwann cells. A variety of cytokines and peptide growth factors, including interleukin-1 (IL-1) and platelet-derived growth factor (PDGF), which are known to increase NGF-mRNA in fibroblasts and astrocytes, failed to do so in Schwann cell cultures. Forskolin (FK), an activator of adenylate cyclase, increased the level of NGF-mRNA eightfold within 3 hr of incubation. The effect of FK on NGF-mRNA was mimicked by analogs of cAMP but not by dideoxyforskolin, an FK derivative not activating adenylate cyclase. Application of norepinephrine and isoproterenol also augmented the NGF-mRNA content. Pretreatment of Schwann cells with N-[2-(methylamino)ethyl]-5- isoquinoline sulfonamide dihydrochloride (H-8), an inhibitor of cyclic- nucleotide-dependent protein kinases, decreased both basal and elevated levels of NGF-mRNA. Ionomycin, a Ca2+ ionophore, and phorbol 12- myristate 13-acetate (TPA), an activator of protein kinase C, potentiated the effect of FK in an H-8-sensitive manner. We show that the action of FK is independent of changes in mRNA stability and of protein synthesis. Thus, in cultured Schwann cells upregulation of NGF- mRNA expression seems to be mainly achieved by a cAMP-triggered transcriptional activation of the NGF gene. Another striking difference between various glial cell types was revealed by application of transforming growth factor beta-1 (TGF-beta 1), which is the strongest inducer of NGF-mRNA in cultured astrocytes (Lindholm et al., 1990). Schwann cells responded to TGF-beta 1 by decreasing basal as well as FK- induced NGF-mRNA levels. Together with previously published work, our results show that cell-type-specific mechanisms not only account for the different control of NGF expression in neurons as compared to glial cells, but also reveal a surprising specificity of regulatory mechanisms in different non-neuronal cell types, even those derived from the same tissue such as fibroblasts and Schwann cells of peripheral nerves.