Korean J Physiol Pharmacol.  2012 Apr;16(2):131-138. 10.4196/kjpp.2012.16.2.131.

Cilostazol Decreases Ethanol-Mediated TNFalpha Expression in RAW264.7 Murine Macrophage and in Liver from Binge Drinking Mice

Affiliations
  • 1Department of Pharmacology, School of Medicine, Catholic University of Daegu, Daegu 705-718, Korea.
  • 2Department of Internal Medicine, Yeungnam University College of medicine, Daegu 705-717, Korea. dreun@ynu.ac.kr

Abstract

Alcoholic hepatitis is a leading cause of liver failure in which the increased production of tumor necrosis factor alpha (TNFalpha) 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 TNFalpha 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 TNFalpha 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 TNFalpha 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. TNFalpha 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 TNFalpha production in liver. These results demonstrated that cilostazol effectively decrease the ethanol-mediated TNFalpha production both in murine macrophage and in liver from binge drinking mice and AMPK may be responsible for the inhibition of TNFalpha production by cilostazol.

Keyword

Alcoholic hepatitis; AMPK; Cilostazol; Macrophage; Tumor necrosis factor alpha
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