Cell-Type-specific Regulation of Nerve Growth Factor (NGF) Synthesis in Non-neuronal Cells

We have previously show" thai after peripheral nerve lesion the synthesis 0' NGF is induced in cells 01 the nerve sheath (Heumann el 81., 19878). Further analysis led 10 the identiflcation 01 growth factars and intracellular mechanisms responsible 10r this induction in sciatic fibroblasts (lind holm el 81., 1988; Hengerer el 81., 1990). The prese"t work aimed al the elucidation of the regulation 0' NGF synthesis in Schwan" cells. A variety 01 cytokines and peptide growth factors, including interleukinl (ILt) and platelet-derived growth factor (PDGF), which are known 10 increase NGF-mRNA in 'ibroblasts and astrocytes, failed to do so in Schwann cell cultures. Forskolin (FK), an activator 01 adenylate cycla8e, increased the level o' 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 0' norepinephrine and isoproterenol also augmented the NGFmRNA content. Pretreatment of Schwann cells with N-(2(methylamlno)ethyll-S-isoquinoline sulfonamide dihydrochloride (H-8), an inhibitor 0' cyclic-nucleotide-dependent protein kinas.s, decreased both basal and elevated levels of NGF-mRNA. lonomycin, a Cau ionophore, and phorbol 12-myristate 13-acetate (TPA), an aClivatoro' prote in 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 HGF gene. Another striking difference between various glial cell types was revealed by application of transforming growth factor 1J-1 (TGF-1J1), which i8 the strongest inducerof NGF-mRNA in cultured astrocytes (Lindholm el 81., 1990). Schwann cells responded 10 TGF-,81 by decreasing basal as weil 8S FK-induced NGF-mRNA levels. Tagether with previously published work, our reaults show that cell-type-specific mechanisms not only account 10r the different control of HGF expression in neurons .s compared