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

Abstract

HighlightsOxidative 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.

In vitro evaluation of the toxicity and underlying molecular mechanisms of Janus Fe3O4‐TiO2 nanoparticles in human liver cells

“…36 In addition, research has also suggested that oxidative stress induced phosphorylation of MAPKs and NF-κB through TAK1 activation can result in increased COX-2. 37 From these results, we conclude that oxidative stress is an important factor for generating COX-2.…”

Free-fatty acid receptor-4 (FFA4) modulates ROS generation and COX-2 expression via the C-terminal β-arrestin phosphosensor in Raw 264.7 macrophages

“…In that study, the FFA4-β-arrestin-2 axis was responsible for sequestration of TAB1 by β-arrestin-2, blocking the TAB1/TAK1 interaction that facilitates NF-κB activity (13). The ability of FFA4-β-arrestin-2 signaling to inhibit TAK1 effects are also of note given the importance of TAK1 in ROS-dependent upregulation of COX-2 (5), signifying that the noted effects of FFA4 on ROS generation may also be mediated, at least in part, by β-arrestin-2, a hypothesis that is confirmed by reduced ability of FFA4-S–Δ340 to decrease ROS generation. However, a curiosity of these data is the lack of effect of FFA4-L-WT, the purported β-arrestin-biased isoform, on inhibition of NF-κB activity, since neither FFA4-L-WT or FFA4-L–Δ356 were able to reduce LPS-mediated NF-κB or ERK1/2 activities, contrary to their ability to reduce PMA-mediated ROS generation.…”

“…Since ROS are known to play a part in increasing expression of pro-inflammatory COX-2 in macrophages and other cell types (5–8), we next assessed the role of FFA4 in modulating COX-2 expression. In untransfected Raw 264.7 macrophages, PMA treatment (1 μM, 4 h) induced COX-2 expression via PKC, as BIMII (10 μM 1 h prior to PMA) completely abolished the effect (Fig 6A).…”

JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis

“…Reduction of ROS can inhibit inflammation in the RA joint, with studies showing that ROS scavengers can reduce oxidative stress in RASFs and can significantly decrease osteoclastogenesis and proinflammatory cytokines in mouse models of arthritis . In addition, ROS induces cyclooxygenase 2 and the key MAPK, NF‐κB, and transforming growth factor β–activated kinase signaling pathways in RASFs , and coculture of RASFs with peripheral blood mononuclear cells increases the number of CD4+CXCR5+ inducible costimulator–positive T cells, an effect mediated in part by increased ROS .…”