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Anti-inflammatory properties of cilostazol: Its interruption of DNA binding activity of NF-B from the Toll-like receptor signaling pathways

Sakamoto, T;Ohashi, W;Tomita, K;Hattori, K;Matsuda, N;Hattori, Y;

Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat ischemic symptoms of peripheral vascular disease. Ample evidence has suggested that cilostazol also exhibits an anti-inflammatory effect, but its anti-inflammatory mechanism is not fully understood. Here, we showed that cilostazol specifically inhibited expression of cytokines, which are induced by nuclear factor-B (NF-B) activation, in RAW264.7 macrophage cells stimulated with different Toll-like receptor (TLR) ligands. Cilostazol was found to significantly reduce TLR-4 and TLR-3 ligands-stimulated NF-B transcriptional activity, which was quantified by luciferase reporter assays. However, cilostazol was without effect on IB degradation and NF-B p65 phosphorylation and nuclear translocation after challenge with the TLR-4 ligand lipopolysaccharide (LPS). Cilostazol did not also prevent the LPS-induced increase in phosphorylated levels of the mitogen-activated protein kinase (MAPK) family. On the other hand, using chromatin immunoprecipitation assays, we demonstrated that cilostazol reduced the LPS-induced transcriptional activities of interleukin-6 and tumor necrosis factor- by preventing the recruitment of NF-B p65 to these gene promoters. When cilostazol was given to mice by oral gavage daily for 7days, LPS-induced aberrant pro-inflammatory cytokine production and end-organ tissue injury were significantly reduced. The results of this study suggest that cilostazol is capable of directly interrupting DNA binding activity of NF-B proteins from the TLR signaling pathways. The therapy to specifically intervene in this pathway may be potentially beneficial for the prevention of different inflammatory disorders. Copyright 2018 Elsevier B.V. All rights reserved.

  • PubMed ID: 30005227