Au(III), Pd(II), Ni(II), and Hg(II) alter NFκB signaling in THP1 monocytic cells

The transcription factor NFκB plays a key role in the tissue inflammatory response. Metal ions released into tissues from biomaterials (e.g., Au, Pd, Ni, Hg) are known to alter the binding of NFκB proteins to DNA, thereby modulating the effect of NFκB on gene activation and, ultimately, the tissue response to biomaterials. Little is known about the effect of these metals on key signaling steps prior to NFκB‐DNA binding such as transcription factor activation or nuclear translocation, yet these steps are equally important to modulation of the pathway. Oxidative stress is known to alter NFκB proteins and is suspected to play a role in metal‐induced NFκB signaling modulation. Our aim in the current study was to assess the effects of sublethal levels of Ni, Hg, Pd, and Au ions on NFκB activation and nuclear translocation in the monocyte, which is acknowledged as an important orchestrator of the biological response to materials and the pathogenesis of chronic disease. Sublethal concentrations of Au(III), Ni(II), Hg(II), and Pd(II) were added to cultures of human THP1 monocytic cells for 72 h. In parallel cultures, lipopolysaccharide (LPS) was added for the last 30 min to activate the monocytic cells. Then cellular cytoplasmic and nuclear proteins were isolated, separated by electrophoresis, and probed for IκBα degradation (activation) and NFκB p65 translocation. Protein levels were digitally quantified and statistically compared. The levels of reactive oxygen species (ROS) in the monocytic cells were measured as a possible mechanism of metal‐induced NFκB modulation. Only Au(III) activated IκBα degradation by itself. Au(III) and Pd(II) enhanced LPS‐induced IκBα degradation, but Hg(II) and Ni(II) suppressed it. Au(III), Ni(II), and Pd(II) activated p65 nuclear translocation without LPS, and all but Ni(II) enhanced LPS‐induced translocation. Collectively, the results suggest that these metal ions alter activation and translocation of NFκB, each in a unique way at unique concentrations. Furthermore, even when these metals had no overt effects on signaling by themselves, all altered activation of signaling by LPS, suggesting that the biological effects of these metals on monocytic function may only be manifest upon activation. None of the metal ions elevated levels of ROS at 72 h, indicating that ROS were probably not direct modulators of the NFκB activation or translocation at this late time point. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res, 2005