Imperatorin Inhibits Proliferation, Migration, and Inflammation via Blocking the NF-?B and MAPK Pathways in Rheumatoid Fibroblast-like Synoviocytes

Rheumatoid arthritis (RA) is a chronic joint inflammatory disease associated with the aberrant activation of fibroblast-like synoviocytes (FLSs). Searching for natural compounds that may suppress the activation of FLSs has become a complementary approach for RA treatment. Here, we investigated the effects and mechanisms of imperatorin (IPT) on proliferation, migration, and inflammation in primary cultured arthritic FLSs. We found that IPT significantly suppressed TNF alpha-induced proliferation and migration of arthritic FLSs, but showed little effect on survival and apoptosis. In addition, IPT treatment significantly reduced the TNF alpha-induced expression of pro-inflammatory cytokines (IL-1 beta, TNF alpha, IL-6, and IL-8) in arthritic FLSs. Further mechanism studies suggested that IPT inhibited the activations of p38 and extracellular signal-regulated kinase (ERK). Also, IPT blocked the nuclear factor of kappa B (NF -kappa B) activation by suppressing the phosphorylation and degradation of IKB alpha, thereby preventing the translocation of p65. Collectively, our results demonstrated that IPT could inhibit the over-activated phenotypes of arthritic FLSs via the mitogen-activated protein kinase (MAPK) (p38 and ERK) and NF -kappa B pathways leading to the down regulation of pro-inflammatory cytokines, which might be beneficial to the anti-proliferative and anti-migratory activities of FLS cells. These findings suggest that IPT has the potential to be developed as a novel agent for RA treatment.