Cytokine and intracellular signaling regulation of tissue factor expression in astrocytes
Cytokine and intracellular signaling regulation of tissue factor expression in astrocytes
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DOI：
10.1016/s0197-0186(99)00147-3
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发表时间：
2000-04-01
影响因子：
4.2
通讯作者：
Callahan, KS
中科院分区：
文献类型：
--
作者：
Klein, BD;White, HS;Callahan, KS
有证据表明，炎性细胞因子如IL-1（β）、TNF α和IL-6参与了包括中风在内的脑血管疾病的发病机制。促成外周组织疾病的细胞因子的一个作用是促凝血受体组织因子（TF）的上调。在中枢神经系统中，星形胶质细胞是表达TF的主要细胞;尽管对TF在这些细胞中如何调节知之甚少。进行实验以评估细胞因子处理对小鼠皮质星形胶质细胞和人星形细胞瘤细胞系（CCF）的原代培养物中TF活性的影响。IL-1 β处理诱导原代星形胶质细胞中TF活性增加2.5倍，诱导星形细胞瘤细胞中TF活性增加3倍。TNF α处理诱导原代星形胶质细胞和星形细胞瘤细胞TF活性增加2.5倍。IL-6上调TF活性2倍，在原代星形胶质细胞，但它没有影响TF活性在星形细胞瘤细胞。调节TF在这些细胞中的表达的信号通路进行了检查，通过使用星形孢菌素，丝氨酸-苏氨酸蛋白激酶的广谱抑制剂，并通过检查鞘磷脂信号通路中的中间体的影响。星形孢菌素抑制原代星形胶质细胞中IL-1（β）诱导的TF活性，但不影响星形细胞瘤细胞中IL-1（β）或TNF α诱导的TF活性。TF活性在星形细胞瘤细胞上调1.5倍以上的组成水平的神经酰胺类似物或鞘磷脂酶，但神经酰胺类似物没有影响TF活性的主要星形胶质细胞。这些结果表明，炎性细胞因子可以上调TF活性的星形胶质细胞和星形细胞瘤CCF细胞系，虽然这两种细胞类型似乎利用不同的信号通路来介导TF的表达。进一步的研究将是重要的，以更完整地定义TF在星形胶质细胞中的信号调节，因为脑TF水平的改变可能在CNS病理生理学中起关键作用。(C)2000爱思唯尔科技有限公司版权所有。
There is evidence that inflammatory cytokines such as IL-1(beta), TNFalpha and IL-6 are involved in the pathogenesis of cerebrovascular disorders including stroke. One action of cytokines that contributes to diseases in peripheral tissues is upregulation of the procoagulant receptor tissue factor (TF). In the CNS, astrocytes are the primary cells that express TF; although little is known about how TF is regulated in these cells. Experiments were performed to evaluate the effect of cytokine treatment on TF activity in primary cultures of murine cortical astrocytes and in the human astrocytoma cell line (CCF). IL-1 beta treatment induced a 2.5-fold increase in TF activity in the primary astrocytes and a 3-fold induction in the astrocytoma cells. TNFalpha treatment induced a 2.5-fold increase in TF activity in both the primary astrocytes and astrocytoma cells. IL-6 upregulated TF activity 2-fold in primary astrocytes, however, it had no effect on TF activity in the astrocytoma cells. The signaling pathways regulating TF expression in these cells were examined by using staurosporine, a broad spectrum inhibitor of serine-threonine protein kinases, and by examining the effects of intermediates in the sphingomyelin signaling pathway. Staurosporine inhibited IL-1(beta)-induced TF activity in the primary astrocytes but did not effect IL-1(beta)- or TNFalpha-induced TF activity in the astrocytoma cells. TF activity in the astrocytoma cells was upregulated 1.5-fold over constitutive levels by a ceramide analogue or the enzyme sphingomyelinase, however the ceramide analogue had no effect on TF activity in the primary astrocytes. These results suggest inflammatory cytokines can upregulate TF activity in astrocytes and the astrocytoma CCF cell line although the two cell types appear to utilize different signaling pathways to mediate TF expression. Further studies will be important to more completely define the signaling regulation of TF in astrocytes since alterations in brain TF levels may play a key role in CNS pathophysiology. (C) 2000 Elsevier Science Ltd. All rights reserved.