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
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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.
KeywordsCotreatment Cilostazol Celecoxib Synovial fibroblast Rheumatoid arthritis
c-Jun NH2-terminal kinase
Synovial fibroblasts from RA patients
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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