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Reactive oxygen species (ROS) are implicated in playing a role in initiating and in propagating the pathogenesis of rheumatoid arthritis (RA). We investigated the mechanism(s) by which essential redox-active trace metals (RATM) may activate gene transcription in synovial fibroblasts. The rabbit fibroblast-like synovial cells which express Toll-like receptor 4 (TLR4), were used as a model system for potentially initiating RA through oxidative stress. Potassium peroxychromate (PPC, Cr⁵⁺), ferrous chloride (FeCl₂, Fe²⁺), and cuprous chloride (CuCl, Cu⁺) at the indicated valency states were used as exogenous pro-oxidants.  These trace metals can induce oxidative stress through TLR4 activation to release inflammatory cytokines and high mobility group box 1 protein. We measured the total expression levels of mitogen-activated protein kinase (MAPK) in the synovial cells and examined the effect of the redox-active trace metals on the time-course production of phosphorylated moieties of MAPK by fluorescence cell-sorting flow cytometry. TLR4 siRNA was used to examine the role of TLR4 in the activator protein -1 (AP-1) signalling activity, and western blots were used to measure the time-course phosphorylation levels of AP-1-activation-related proteins. While the redox-active trace metals increased intracellular ROS that can induce oxidative stress, they also induced MAPK kinases to upregulate the expression of AP-1 proteins in synovial cells. Our results show that redox-active trace metal/TLR4-coupled activation may contribute to the pathogenesis of RA. The signaling pathway by which inflammation and its destructive sequel may occur in RA through synovial cells underlies the need for developing therapeutic agents to serve in individualized RA therapy with a consideration for the underlying mechanism(s) of its pathogenesis.