Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages
Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages
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DOI：
10.1172/jci119812
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发表时间：
1997-12-01
影响因子：
15.9
通讯作者：
Singh, I
中科院分区：
文献类型：
--
作者：
Pahan, K;Sheikh, FG;Singh, I
本研究探讨了甲羟戊酸抑制剂在大鼠原代星形胶质细胞、小胶质细胞和巨噬细胞中激活NF-κ β和诱导型一氧化氮合酶（iNOS）和细胞因子（TNF-α、IL-1 β和IL-6）的作用。发现洛伐他汀和苯乙酸钠（NaPA）抑制大鼠原代星形胶质细胞中LPS和精氨酸介导的NO产生和iNOS表达;这种抑制不是由于甲羟戊酸途径的终产物的消耗（例如，胆固醇和泛醌）。洛伐他汀对甲羟戊酸和焦磷酸法呢酯诱导的LPS诱导的iNOS表达的抑制作用以及NaPA对焦磷酸法呢酯诱导的LPS诱导的iNOS表达的抑制作用的逆转，提示法呢酯化在LPS介导的iNOS诱导中的作用。FPT抑制剂II（Ras法尼基蛋白转移酶的抑制剂）对LPS介导的iNOS诱导的抑制表明p21（ras）或其它蛋白的法尼基化调节iNOS的诱导。在星形胶质细胞中，洛伐他汀、NaPA和FPT抑制剂II对LPS介导的NF-κ β活化的抑制表明，所观察到的iNOS表达抑制是通过抑制NF-κ β活化介导的。除iNOS外，洛伐他汀和NaPA还抑制LPS诱导的大鼠原代星形胶质细胞、小胶质细胞和巨噬细胞中TNF-α、IL-1 β和IL-6的表达。这项研究描绘了一种新的甲羟戊酸途径在控制大鼠星形胶质细胞，小胶质细胞和巨噬细胞中iNOS和不同细胞因子的表达中的作用，这可能对开发抗细胞因子和NO介导的神经退行性疾病的治疗方法很重要。
This study explores the role of mevalonate inhibitors in the activation of NF-k beta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha, IL-1 beta, and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS- and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes; this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21(ras) or other proteins regulates the induction of iNOS. Inhibition of LPS-mediated activation of NF-k beta by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-k beta activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-alpha, IL-1 beta, and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocyte, microglia, and macrophages that may be important in developing therapeutics against cytokine- and NO-mediated neurodegenerative diseases.