Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells

Highlights • Oxidative stress in the arthritis joint is involved in generating mediators for inflammation. • Oxidative stress-induced expression of Cox-2 was mediated by MAPKs and NF-κB. • ROS-induced MAPKs and NF-κB were attenuated by inhibition of MAPKKK TAK1. • Inhibition of TAK1 activity resulted in reduced expression of Cox-2 and PGE2. • ROS-induced TAK1 activation and Cox-2 expression was inhibited by antioxidants N-acetyl cysteamine and hyaluronic acid.
Oxidative stress within the arthritis joint has been indicated to be involved in generating mediators for tissue degeneration and inflammation. COX-2 is a mediator in inflammatory action, pain and some catabolic reactions in inflamed tissues. Here, we demonstrated a direct relationship between oxidative stress and Cox-2 expression in the bovine synovial fibroblasts. Furthermore, we elucidated a novel mechanism, in which oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation and resulted in increased Cox-2 and prostaglandin E2 expression. Finally, we demonstrated that ROS-induced Cox-2 expression was inhibited by supplementation of an antioxidant such as N-acetyl cysteamine and hyaluronic acid in vitro and in vivo. From these results, we conclude that oxidative stress is an important factor for generation of Cox-2 in synovial fibroblasts and thus its neutralization may be an effective strategy in palliative therapy for chronic joint diseases.