Pahan K, Sheikh F G, Namboodiri A M, Singh I
Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
J Clin Invest. 1997 Dec 1;100(11):2671-9. doi: 10.1172/JCI119812.
This study explores the role of mevalonate inhibitors in the activation of NF-kbeta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha, IL-1beta, 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-kbeta by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-kbeta activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-alpha, IL-1beta, 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 astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokine- and NO-mediated neurodegenerative diseases.
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核因子-κB（NF-κB）以及诱导诱导型一氧化氮合酶（iNOS）和细胞因子（肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6）中的作用。研究发现洛伐他汀和苯乙酸钠（NaPA）可抑制大鼠原代星形胶质细胞中脂多糖（LPS）和细胞因子介导的一氧化氮（NO）生成及iNOS表达；这种抑制并非由于甲羟戊酸途径终产物（如胆固醇和泛醌）的耗竭。然而，甲羟戊酸和法尼基焦磷酸可逆转洛伐他汀对LPS诱导的iNOS表达的抑制作用，法尼基焦磷酸可逆转NaPA对LPS诱导的iNOS表达的抑制作用，这表明法尼基化在LPS介导的iNOS诱导中起作用。Ras法尼基蛋白转移酶抑制剂FPT抑制剂II对LPS介导的iNOS诱导的抑制作用表明，p21（ras）或其他蛋白的法尼基化调节iNOS的诱导。洛伐他汀、NaPA和FPT抑制剂II对星形胶质细胞中LPS介导的NF-κB激活的抑制表明，观察到的iNOS表达抑制是通过抑制NF-κB激活介导的。除iNOS外，洛伐他汀和NaPA还抑制大鼠原代星形胶质细胞、小胶质细胞和巨噬细胞中LPS诱导的肿瘤坏死因子-α、白细胞介素-1β和白细胞介素-6的表达。本研究阐明了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和不同细胞因子表达方面的新作用，这可能对开发针对细胞因子和NO介导的神经退行性疾病的治疗方法具有重要意义。
