Signal transduction pathways mediating astrocyte IL-6 induction by IL-1 beta and tumor necrosis factor-alpha.
Signal transduction pathways mediating astrocyte IL-6 induction by IL-1 beta and tumor necrosis factor-alpha.
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DOI：
10.4049/jimmunol.152.2.841
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发表时间：
1994-01
影响因子：
4.4
通讯作者：
J. G. Norris;L. Tang;S. M. Sparacio;E. Benveniste
中科院分区：
文献类型：
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作者：
J. G. Norris;L. Tang;S. M. Sparacio;E. Benveniste
星形胶质细胞的一个免疫功能是产生IL-6。中枢神经系统（CNS）内IL-6的合成可产生几种不同的反应，作用于胶质细胞、神经元和浸润脑组织的淋巴细胞，其中一些作用与中枢神经系统自身免疫性疾病有关。星形胶质细胞中的IL-6基因表达受细胞因子、感染因子、神经肽和神经递质调控，这些刺激大多协同作用。为了研究这些不同因素在控制IL-6产生中的整合作用，我们利用新生大鼠星形胶质细胞研究了潜在信号转导过程的参与。我们关注的是与IL-1 β和tnf - α刺激IL-6基因表达相关的信号转导。我们的研究结果表明，与蛋白激酶C （PKC）相关的刺激，如PMA和钙离子载体A23187，增加了IL-6的表达，而PKC的药物抑制剂抑制了IL-1 β和tnf - α对IL-6的诱导。此外，IL-1 β和tnf - α都能刺激星形胶质细胞中的PKC活性。cAMP途径的刺激物，如霍乱毒素、福斯克林和二丁基cAMP，也能诱导星形胶质细胞IL-6基因表达。然而，抑制cAMP通路效应蛋白激酶A并没有减少星形胶质细胞IL-6基因表达对IL-1 β或tnf - α的诱导，而且cAMP的ELISA检测到cAMP合成对这些细胞因子的反应只有非常小的增加。这些数据表明，尽管cAMP确实激活星形胶质细胞IL-6基因表达，但PKC途径在IL-1 β和tnf - α刺激星形胶质细胞IL-6基因表达中起主要作用。
One immune function of astrocytes is IL-6 production. Synthesis of IL-6 within the central nervous system (CNS) can produce several different responses, acting on glia, neurons, and lymphocytes infiltrating brain tissue, and some of these effects are associated with CNS autoimmune disease. IL-6 gene expression in astrocytes is regulated by cytokines, infectious agents, neuropeptides, and neurotransmitters, and most of these stimuli interact synergistically. To examine the integration of these diverse factors in the control of IL-6 production, we have studied the involvement of underlying signal transduction processes using neonatal rat astrocytes. We have focused on signal transduction related to the stimulation of IL-6 gene expression by IL-1 beta and TNF-alpha. Our results indicate that stimuli related to protein kinase C (PKC), such as PMA and calcium ionophore A23187, increase IL-6 expression, whereas pharmacologic inhibitors of PKC inhibit IL-6 induction by IL-1 beta and TNF-alpha. Furthermore, both IL-1 beta and TNF-alpha stimulate PKC activity in astrocytes. Stimulators of the cAMP pathway, such as cholera toxin, forskolin, and dibutyryl cAMP, also induced astrocyte IL-6 gene expression. However, inhibition of the cAMP pathway effector, protein kinase A, did not reduce the induction of astrocyte IL-6 gene expression in response to IL-1 beta or TNF-alpha, and an ELISA for cAMP detected only very small increases in cAMP synthesis in response to these cytokines. These data suggest that although cAMP does activate astrocyte IL-6 gene expression, it is the PKC pathway that plays a primary role in the stimulation of astrocyte IL-6 gene expression by IL-1 beta and TNF-alpha.