Cilostazol inhibits monocytic cell adhesion to vascular endothelium via upregulation of cAMP.
OBJECTIVE
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 microM) for 48 hours. The cells were then perfused over TNF-alpha (5 microg/mL for 4 hours)-stimulated monolayers of human umbilical vein endothelial cells (HUVECs) at shear stress of 1.0 dyen/cm(2).


RESULTS
TNF-alpha-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-alpha-activated HUVECs was markedly reduced (3.63+/-0.55/HPF) when THP-1 cells were incubated in the presence of cilostazol at 5 microM. 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.


CONCLUSIONS
These data suggest that cilostazol has a potential anti-inflammatory effect on monocyte-endothelial interactions via the upregulation of intracellular cAMP.
Mori
Daisuke
D
Life Science and Bioethics Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
Ishii
Hideto
H
Kojima
Chiari
C
Nitta
Noriko
N
Nakajima
Katsuyuki
K
Yoshida
Masayuki
M
D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D006801:Humans; D007118:Immunoassay; D016023:Integrins / Q000096:biosynthesis / Q000187:drug effects; D036904:Leukocyte Rolling / Q000187:drug effects; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D016023:Integrins; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D000242:Cyclic AMP; D000077407:Cilostazol