MECHANISMS OF NERVE GROWTH-FACTOR MESSENGER-RNA REGULATION BY INTERLEUKIN-1-BETA IN HIPPOCAMPAL CULTURES - ROLE OF 2ND MESSENGERS
MECHANISMS OF NERVE GROWTH-FACTOR MESSENGER-RNA REGULATION BY INTERLEUKIN-1-BETA IN HIPPOCAMPAL CULTURES - ROLE OF 2ND MESSENGERS
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DOI：
10.1002/jnr.490330106
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发表时间：
1992-09-01
影响因子：
4.2
通讯作者：
PERSSON, H
中科院分区：
文献类型：
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作者：
FRIEDMAN, WJ;ALTIOK, N;PERSSON, H
细胞因子如白细胞介素-1在创伤后的脑中发现，调节海马培养物中神经生长因子（NGF）mRNA和蛋白的表达。我们研究了IL-1-β调节海马细胞中NGF的可能机制。IL-1-β对NGF mRNA的诱导作用被受体拮抗剂阻断，表明这种作用是受体介导的。IL-1-β以时间依赖性方式引起c-fos mRNA的显著诱导和c-jun mRNA的轻微升高，这可能在NGF mRNA的诱导中起作用。我们研究了特定的第二信使通路是否参与介导海马中IL-1-β的作用。用毛喉素激活cAMP或用8-Br-cAMP处理对NGF mRNA水平没有影响。此外，海马培养物暴露于IL-1-β诱发cAMP水平没有变化，表明该第二信使系统在这些细胞中IL-1-β对NGF表达的调节中几乎没有作用。此外，白细胞介素-1引起膜磷酸肌醇营业额没有变化，也没有影响细胞内钙水平。用佛波醇酯PMA处理细胞培养物引起NGF mRNA的增加，表明蛋白激酶C（PKC）的激活可能介导NGF mRNA的表达。然而，PMA脱敏PKC的培养物的长期治疗并没有消除IL-1-β诱导的NGF mRNA。因此，IL-1-β似乎没有通过cAMP、Ca 2+或PKC亚型激活NGF表达，而PKC亚型被延长的PMA处理下调。然而，磷酸化事件可能参与了信号转导机制，因为用冈田酸抑制蛋白磷酸酶2a的处理增强了IL-1-β对NGF mRNA的诱导。所呈现的结果表明，IL-1-β通过其受体起作用以诱导NGF表达的上升。识别特定的第二信使途径仍然难以捉摸，然而，磷酸化事件似乎是中介。此外，c-fos和c-jun的诱导可能代表了IL-1-β和PMA等不同信号激活NGF基因表达的最终共同途径。
Cytokines such as interleukin-1, which are found in the brain after trauma, regulate expression of nerve growth factor (NGF) mRNA and protein in hippocampal cultures. We have investigated possible mechanisms by which Il-1-beta regulates NGF in hippocampal cells. The induction of NGF mRNA by Il-1-beta was blocked by a receptor antagonist indicating that this effect is receptor mediated. Il-1-beta elicited a dramatic induction of c-fos mRNA and a slight elevation of c-jun mRNA in a time dependent manner which may allow for a role in the induction of NGF mRNA expression. We examined whether specific second messenger pathways were involved in mediating the action of Il-1-beta in the hippocampus. Activation of cAMP with forskolin or treatment with 8-Br-cAMP had no effect on NGF mRNA levels. Moreover, exposure of hippocampal cultures to Il-1-beta evoked no change in cAMP levels, indicating that this second messenger system played little or no role in the regulation of NGF expression by Il-1-beta in these cells. Further, interleukin-1 elicited no change in membrane inositol phosphate turnover, nor did it affect intracellular calcium levels. Treatment of cell cultures with the phorbol ester PMA elicited an increase in NGF mRNA, suggesting that activation of protein kinase C (PKC) may mediate NGF mRNA expression. However, prolonged treatment of cultures with PMA to desensitize PKC did not eliminate the Il-1-beta induction of NGF mRNA. Il-1-beta, therefore, did not appear to activate NGF expression via cAMP, Ca2+, or a PKC isoform that is downregulated by prolonged PMA treatment. However, a phosphorylation event may be involved in the signal transduction mechanism, as treatment with okadaic acid to inhibit protein phosphatase 2a potentiated the induction of NGF mRNA by Il-1-beta. The results presented indicate that Il-1-beta acts via its receptor to induce a rise in NGF expression. Identification of the specific second messenger pathway has remained elusive; however, a phosphorylation event appears to be intermediary. Moreover, the induction of c-fos and c-jun may represent a final common path in activation of NGF gene expression by different signals such as Il-1-beta and PMA.