The role of cytokines in the depression of CYP1A activity using cultured astrocytes as an in vitro model of inflammation in the central nervous system
The role of cytokines in the depression of CYP1A activity using cultured astrocytes as an in vitro model of inflammation in the central nervous system
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DOI：
10.1124/dmd.30.1.42
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发表时间：
2002-01-01
影响因子：
3.9
通讯作者：
Renton, KW
中科院分区：
文献类型：
--
作者：
Nicholson, TE;Renton, KW
感染和炎症对肝细胞色素P450酶的相互作用和调节在临床环境和动物模型中都有很好的描述。最近的证据发现，中枢神经系统（CNS）的炎症会导致大脑和肝脏中细胞色素P450活性的改变。用细菌内毒素脂多糖（LPS）诱导培养的星形胶质细胞的炎症反应作为CNS炎症模型。这种炎症反应涉及一系列免疫介质，如急性期细胞因子、一氧化氮、前列腺素类产物和活性氧。据推测，炎症过程中释放的细胞因子可调节细胞色素P450特异性亚型的表达，导致活性水平改变。在向星形胶质细胞培养物中加入LPS后，高水平的细胞因子肿瘤坏死因子-a和白细胞介素-1 β被释放到培养基中。当这些相同的细胞因子直接加入到培养物中时，它们也能够调节CYP 1A活性水平。同时向星形胶质细胞中加入地塞米松阻断了细胞因子的释放和CYP 1A活性的改变，从而支持了这些细胞因子在这种反应中的作用。这些结果提供的证据表明，急性期细胞因子介导的LPS诱导的抑郁症的CYP 1A活性在培养的星形胶质细胞的参与。
The interaction and modulation of hepatic cytochrome P450 enzymes by infection and inflammation has been well described both in clinical settings and in animal models. Recent evidence found that inflammation in the central nervous system (CNS) leads to alterations in cytochrome P450 activity in both brain and liver. The bacterial endotoxin lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured astrocytes as a model of CNS inflammation. This inflammatory response involves a range of immune mediators, such as acute phase cytokines, nitric oxide, prostanoid products, and reactive oxygen species. It is hypothesized that cytokines, released during inflammation, act to modulate the expression of specific isoforms of cytochrome P450 resulting in altered activity levels. High levels of the cytokines tumor necrosis factor-a and interleukin-1 beta were released into culture medium after the addition of LPS to astrocyte cultures. When these same cytokines were added directly to the cultures, they also were able to modulate levels of CYP1A activity. The concurrent addition of dexamethasone to astrocytes blocked both the cytokine release and the alteration of CYP1A activity, thus supporting a role for these cytokines in this response. These results provide evidence suggesting an involvement of acute phase cytokines in mediating the LPS-induced depression of CYP1A activity in cultured astrocytes.