WIN-34B May Have Analgesic and Anti-Inflammatory Effects by Reducing the Production of Pro-Inflammatory Mediators in Cells via Inhibition of IkB Signaling Pathways

摘要

WIN-34B showed analgesic and anti-inflammatory effects in various animal models of pain and osteoarthritis. However, the molecular mechanism by which WIN-34B inhibits pain and inflammation in vivo remains to be elucidated. We investigated the molecular mechanisms of the actions of WIN-34B using various in vitro models using fibroblast-like synoviocytes from patients with rheumatoid arthritis (RA FLSs), RAW264.7 cells and peritoneal macrophages. WIN-34B inhibited the level of IL-6, PGE_2, and MMP-13 in IL-1 beta-stimulated RA FLSs in a dose-dependent manner. The mRNA levels were also inhibited by WIN-34B. The level of PGE_2, NO, IL-1 beta, and TNF-a were inhibited by WIN-34B at different concentrations in LPS-stimulated RAW264.7 cells. The production of NO and PGE_2 was inhibited by WIN-34B in a dose-dependent manner in LPS-stimulated peritoneal macrophages. All of these effects were comparable to the positive control, celecoxib or indomethacin. IkB signaling pathways were inhibited by WIN-34B, and the migration of NF-kB into the nucleus was inhibited, which is consistent with the degradation of hcB-a. Taken together, the results suggest that WIN-34B has potential as a therapeutic drug to reduce pain and inflammation by inhibiting the production of pro-inflammatory mediators.