, Volume 27, Issue 6, pp 1205–1216 | Cite as

Cilostazol add-on therapy for celecoxib synergistically inhibits proinflammatory cytokines by activating IL-10 and SOCS3 in the synovial fibroblasts of patients with rheumatoid arthritis

  • Yi Sle Lee
  • Sang Yeob Lee
  • So Youn Park
  • Sung Won Lee
  • Ki Whan Hong
  • Chi Dae KimEmail author
Original Article


Cilostazol (an inhibitor of phosphodiesterase type III) has potent anti-inflammatory effects, and celecoxib (a COX-2 specific inhibitor) has been reported to improve the unsatisfactory profile of NSAIDs. This study investigated the synergistic anti-arthritic potential of a multitarget-based cotreatment, in which cilostazol was used as an add-on therapy for celecoxib, using the synovial fibroblasts of RA patients (RASFs). Increased COX-2 protein expression and PGE2 synthesis by LPS (1 μg/ml) were significantly and synergistically attenuated by cotreatment with 3 μM cilostazol and 30 μM celecoxib, whereas monotherapy with either cilostazol or celecoxib showed little effects. IL-10 mRNA levels in LPS-treated RASFs were moderately increased by pretreating cilostazol (1–10 μM) or celecoxib (10–50 μM) monotherapy, but 3 μM of cilostazol add-on for 30 μM celecoxib treatment synergistically increased IL-10 mRNA levels and IL-10 release to culture media. Cilostazol and celecoxib cotreatment similarly showed synergistic increase in SOCS3 mRNA levels. Accordingly, LPS-induced increases in IL-1β and IL-6 mRNA and TNF-α release were significantly and synergistically diminished by cilostazol and celecoxib cotreatment. Moreover, synovial cell proliferation was significantly suppressed by cotreatment. Summarizing, cotreatment with cilostazol and celecoxib exhibited a synergistic increase in IL-10 production and SOCS3 expressions, thereby resulted in synergistic decreases in IL-1β mRNA, IL-6 mRNA expression and TNF-α synthesis in association with synergistic decreases in COX-2 and PGE2 protein expression in the RA synovial fibroblasts. In conclusion, these observations suggest low concentrations of cilostazol and celecoxib cotreatment may ensure a synergistic anti-arthritic potential.


Cotreatment Cilostazol Celecoxib Synovial fibroblast Rheumatoid arthritis 





Fibroblast-like synoviocytes




c-Jun NH2-terminal kinase


Matrix metalloproteinases


Prostaglandin E2


Synovial fibroblasts from RA patients


Rheumatoid arthritis


Suppressor of cytokine signaling


Signal transducers and activators of transcription



This study was supported by the National Research Foundation of Korea (NRF-2016R1C1B2007691) and the Medical Research Center (MRC) Program through the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2015R1A5A2009656).

Compliance with ethical standards

Conflict of interest

The authors declare no potential conflicts of interest.


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Yi Sle Lee
    • 1
    • 2
  • Sang Yeob Lee
    • 4
  • So Youn Park
    • 1
    • 2
  • Sung Won Lee
    • 4
  • Ki Whan Hong
    • 1
  • Chi Dae Kim
    • 1
    • 2
    • 3
    Email author
  1. 1.Gene and Cell Therapy Research Center for Vessel-associated DiseasesPusan National UniversityYangsan-siRepublic of Korea
  2. 2.Department of Pharmacology, School of MedicinePusan National UniversityYangsan-siRepublic of Korea
  3. 3.Research Institute for Convergence of Biomedical Science and TechnologyPusan National University Yangsan HospitalGyeongnamRepublic of Korea
  4. 4.Department of Internal Medicine, College of MedicineDong-A UniversityBusanRepublic of Korea

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