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.
Park
Won Sun
WS
Department of Physiology, Kangwon National University School of Medicine, Chuncheon 200-701, South Korea.
Jung
Won-Kyo
WK
Lee
Da-Young
DY
Moon
Chisook
C
Yea
Sung Su
SS
Park
Sae-Gwang
SG
Seo
Su-Kil
SK
Park
Cheol
C
Choi
Yung Hyun
YH
Kim
Gi-Young
GY
Choi
Jung Sik
JS
Choi
Il-Whan
IW
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D012772:Shock, Septic / Q000517:prevention & control*; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D013777:Tetrazoles; D000242:Cyclic AMP; D020928:Mitogen-Activated Protein Kinases; D000077407:Cilostazol