Transcriptional and Posttranscriptional Mechanisms Involved in the Interleukin-1, Steroid, and Protein Kinase C Regulation of Nerve Growth Factor in Cortical Astrocytes


Address correspondence and reprint requests to Dr. B. C. Wise at Fidia-Georgetown Institute for the Neurosciences, Georgetown University Medical Center, 3900 Reservoir Road, N.W., Washington, D.C. 20007, U.S.A.


Abstract: Neonatal rat cortical astrocytes in primary culture synthesize and secrete nerve growth factor (NGF). Treatment of astrocytes with interleukin-1β (IL-1) or the protein kinase C (PKC) activator 12-O-tetradecanoylphorbol 13-acetate (TPA) increased NGF mRNA content by six- to 10-fold, followed in time by increases in cell content and cell secretion of NGF. Dexamethasone potently inhibited the effects of IL-1 and TPA on astroglial cell NGF expression. The action of IL-1 was not mediated by PKC because treatment of cells with maximal concentrations of both IL-1 and TPA gave an additive increase in NGF mRNA content and NGF secretion, and because down-regulating PKC activity failed to inhibit the stimulatory effects of IL-1. Moreover, both agents increased NGF gene transcription in nuclear run-on assays, but only IL-1 significantly stabilized the NGF mRNA. An analysis of the effects of IL-1 and TPA on immediate early gene expression indicated that IL-1 preferentially induced c-jun gene expression, whereas TPA greatly increased c-fos and zif/268 gene expression. These results suggest that IL-1 activates c-jun and NGF gene expression, and NGF mRNA stabilization in astrocytes by a distinct PKC-independent signaling pathway.