Kaempferol inhibits IL???1β???induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX???2, PGE2 and MMPs

Inflammatory cytokines, matrix metalloproteinases (MMPs) and cyclooxygenase (COX)?2 released from rheumatoid arthritis synovial fibroblasts (RASFs) are involved in the destruction of both articular bone and cartilage. Kaempferol has been reported to act as an antioxidant and anti?inflammatory agent by inhibiting nitric oxide synthase and COX enzymes. The aim of the present study was to determine the effects of kaempferol on the interleukin?1β (IL?1β)?induced proliferation of RASFs and the production of MMPs, COX and prostaglandin E2 (PGE2) by RASFs. The proliferation of the RASFs stimulated with IL?1β and treated with/without kaempferol was evaluated by CCK?8 assay. The expression of MMPs, TIMP metallopeptidase inhibitor?1 (TIMP?1), COXs, PGE2 and that of intracellular MAPK signaling molecules, including p?ERK, p?p38, p?JNK and nuclear factor?κB (NF?κB) was examined by immunoblotting or semi?quantitative reverse transcription?polymerase chain reaction (RT?PCR) and ELISA under the conditions described above. Kaempferol inhibited the proliferation of both unstimulated and IL?1β?stimulated RASFs, as well as the mRNA and protein expression of MMP?1, MMP-3, COX?2 and PGE2 induced by IL?1β. Kaempferol also inhibited the phosphorylation of ERK?1/2, p38 and JNK, as well as the activation of NF?κB induced by IL?1β. These results indicate that kaempferol inhibits synovial fibroblast proliferation, as well as the production of and MMPs, COX?2 and PGE2, which is involved in articular inflammation and destruction in rheumatoid arthritis (RA). Our data suggest that kaempferol may be a novel therapeutic agent for the treatment of RA.The present study was supported by a grant from the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Korea (A084144)