Cilostazol protects mice against endotoxin shock and attenuates LPS-induced cytokine expression in RAW 264.7 macrophages via MAPK inhibition and NF-kappaB inactivation: not involved in cAMP mechanisms.

Cilostazol, a phosphodiesterase 3 inhibitor, is a platelet aggregation inhibitor and vasodilator that is useful for treating intermittent claudication. Experimental studies have shown that cilostazol has potent anti-inflammatory effects. In the present study, we examined the effect of cilostazol on lipopolysaccharide (LPS)-induced inflammatory cytokines in macrophages and endotoxin shock in mice. Our results indicate that cilostazol inhibits LPS-stimulated up-regulation of pro-inflammatory cytokines in a concentration-dependent manner without appreciable cytotoxicity in RAW 264.7 cells. Cilostazol did not enhance intracellular cyclic AMP (cAMP) levels. To further elucidate the mechanism responsible for the inhibition of production of pro-inflammatory mediators by cilostazol, we examined the effect of cilostazol on LPS-stimulated nuclear factor-kappaB (NF-kappaB) activation and phosphorylation of mitogen-activated protein kinases (MAPK). Our results clearly indicated that cilostazol treatment reduced on of MAPK phosphorylation and NF-kappaB activity, and that the inhibitory effect of cilostazol is independent of the cAMP pathway. In an animal model, cilostazol protected c57BL/6 mice from LPS-induced endotoxin shock, possibly through inhibition of the production of pro-inflammatory cytokines. In conclusion, cilostazol inhibits LPS-stimulated production of pro-inflammatory cytokines and protects mice from endotoxin shock, suggesting that cilostazol may be a novel therapeutic agent for the prevention of various inflammatory diseases.