Transcriptional and posttranscriptional mechanisms involved in the interleukin-1, steroid, and protein kinase C regulation of nerve growth factor in cortical astrocytes.
Neonatal rat cortical astrocytes in primary culture synthesize and secrete nerve growth factor (NGF). Treatment of astrocytes with interleukin-1 beta (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.
Fidia-Georgetown Institute for the Neurosciences, Georgetown University Medical Center, Washington, D.C. 20007.
S P
SP
Pshenichkin
A M
AM
Szekely
B C
BC
Wise
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology*; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000187:drug effects; D006801:Humans; D017874:Immediate-Early Proteins; D007375:Interleukin-1 / Q000494:pharmacology*; D009414:Nerve Growth Factors / Q000096:biosynthesis*; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000187:drug effects; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D007375:Interleukin-1; D009414:Nerve Growth Factors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; D003907:Dexamethasone; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate