Department of Pharmacology, School of Medicine, Catholic University of Daegu, Daegu 705-718, Korea.
Korean J Physiol Pharmacol. 2012 Apr;16(2):131-8. doi: 10.4196/kjpp.2012.16.2.131. Epub 2012 Apr 24.
Alcoholic hepatitis is a leading cause of liver failure in which the increased production of tumor necrosis factor α (TNFα) plays a critical role in progression of alcoholic liver disease. In the present study, we investigated the effects of cilostazol, a selective inhibitor of type III phosphodiesterase on ethanol-mediated TNFα production in vitro and in vivo, and the effect of cilostazol was compared with that of pentoxifylline, which is currently used in clinical trial. RAW264.7 murine macrophages were pretreated with ethanol in the presence or absence of cilostazol then, stimulated with lipopolysacchride (LPS). Cilostazol significantly suppressed the level of LPS-stimulated TNFα mRNA and protein with a similar degree to that by pentoxifylline. Cilostazol increased the basal AMP-activated protein kinase (AMPK) activity as well as normalized the decreased AMPK by LPS. AICAR, an AMPK activator and db-cAMP also significantly decreased TNFα production in RAW264.7 cells, but cilostazol did not affect the levels of intracellular cAMP and reactive oxygen species (ROS) production. The in vivo effect of cilostazol was examined using ethanol binge drinking (6 g/kg) mice model. TNFα mRNA and protein decreased in liver from ethanol gavaged mice compared to that from control mice. Pretreatment of mice with cilostazol or pentoxifylline further reduced the TNFα production in liver. These results demonstrated that cilostazol effectively decrease the ethanol-mediated TNFα production both in murine macrophage and in liver from binge drinking mice and AMPK may be responsible for the inhibition of TNFα production by cilostazol.
酒精性肝炎是肝衰竭的一个主要原因，其中肿瘤坏死因子α（TNFα）的过度产生在酒精性肝病的进展中起着关键作用。在本研究中，我们研究了西洛他唑（一种选择性的 III 型磷酸二酯酶抑制剂）对体外和体内乙醇介导的 TNFα产生的影响，并将西洛他唑的作用与目前正在临床试验中使用的己酮可可碱进行了比较。RAW264.7 小鼠巨噬细胞先用乙醇预处理，然后用脂多糖（LPS）刺激。西洛他唑显著抑制 LPS 刺激的 TNFα mRNA 和蛋白水平，与己酮可可碱的抑制程度相似。西洛他唑增加了基础 AMP 激活蛋白激酶（AMPK）活性，并使 LPS 降低的 AMPK正常化。AMPK 激活剂 AICAR 和 db-cAMP 也显著降低 RAW264.7 细胞中的 TNFα 产生，但西洛他唑不影响细胞内 cAMP 和活性氧（ROS）的产生水平。使用乙醇 binge 饮酒（6 g/kg）小鼠模型检查了西洛他唑的体内作用。与对照小鼠相比，乙醇灌胃小鼠的肝脏中 TNFα mRNA 和蛋白减少。用西洛他唑或己酮可可碱预处理进一步降低了肝脏中的 TNFα 产生。这些结果表明，西洛他唑可有效减少乙醇介导的 TNFα产生，无论是在小鼠巨噬细胞中还是在 binge 饮酒小鼠的肝脏中，并且 AMPK 可能是西洛他唑抑制 TNFα产生的原因。
