Cilostazol Inhibits Monocytic Cell Adhesion to Vascular Endothelium Via Upregulation of cAMP

Aim: Cilostazol is clinically used as an inhibitor of platelet aggregation. Although several reports have demonstrated its anti-inflammatory effect, its effect on monocytes and their adhesive interaction to vascular endothelium remains unclear. We thus examined the potential role of cilostazol towards monocyte endothelial interaction under physiological flow conditions. Methods: THP-1 cells, a monocytic cell line, were pretreated with cilostazol (5 µM) for 48 hours. The cells were then perfused over TNF-alpha (5 µg/mL for 4 hours)-stimulated monolayers of human umbilical vein endothelial cells (HUVECs) at shear stress of 1.0 dyen/cm2. Results: TNF-α-activated HUVECs supported significantly more monocyte adhesion to HUVECs (7.32±1.25/HPF) compared to inactivated HUVECs (0.74±0.15/HPF), and the amount of adhesion to TNF-α-activated HUVECs was markedly reduced (3.63±0.55/HPF) when THP-1 cells were incubated in the presence of cilostazol at 5 µM. Interestingly, surface expressions of integrins were not dramatically changed after cilostazol treatment. Intracellular concentration of cAMP was significantly increased after cilostazol treatment, and treatment with Forskolin and Dibutyryl-cAMP, potent inducers of cAMP, dramatically increased THP-1 adhesion to HUVECs. Conclusion: These data suggest that cilostazol has a potential anti-inflammatory effect on monocyte-endothelial interactions via the upregulation of intracellular cAMP.