Anti-inflammatory profile of cilostazol in Toll-like receptor ligands-stimulated macrophages and endotoxemic mouse

[Speaker] Takuya Sakamoto:1
[Co-author] Kengo Tomita:1, Wakana Ohashi:1, Yuichi Hattori:1
1:Department of Molecular and Medical Pharmacology, University of Toyama, Japan

 Cilostazol, a selective inhibitor of phosphodiesterase III with anti-platelet aggregation and vasodilatory properties, is used for treatment of ischemic symptoms of peripheral vascular diseases. Cilostazol has drawn a great deal of interest because of its potent anti-inflammatory effect. The anti-inflammatory action of cilostazol is indicated to be associated with NF-κB inactivation. This study aimed to identify the mechanism by which cilostazol modifies NF-κB signaling as a potential locus for its therapeutic intervention using the mouse macrophage cell line RAW264.7. We also examined whether oral administration of cilostazol can prevent endotoxemic organ injury.

[Method and results]
 When RAW264.7 was stimulated with the Toll-like receptor (TLR)-4 ligand lipopolysaccharide (LPS) and the TLR2 ligand peptidoglycan, treatment with cilostazol suppressed the upregulation of gene expression of TNF-α, IL-1β, IL-6, and MCP-1. Cilostazol treatment also inhibited the increase in IL-6 mRNA in the TLR3 ligand poly(I:C)-stimulated RAW264.7. However, cilostazol was without effect on the IP-10 and RANTES genes which were upregulated by LPS and poly(I:C). Cilostazol significantly reduced NF-κB luciferase activity but did not substantially affect IκB-α degradation and NF-κB nuclear translocation in LPS-stimulated RAW264.7. When cilostazol (50 and 200 mg/kg) was administered by oral gavage to mice for 7 days, the development of major end-organ (that is, lung, liver, and kidney) injury induced by intravenous injection of LPS was significantly reduced.

 Our results demonstrate that cilostazol inhibits the MyD88-dependent NF-κB pathway and protects mice from LPS-induced organ injury, suggesting that cilostazol could have potential for the treatment of patients with septic multiorgan dysfunction.

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