Cadmium ions induce monocytic production of tumor necrosis factor-alpha by inhibiting mitogen activated protein kinase dephosphorylation

Cadmium ions (Cd2+) are carcinogenic and have cytotoxic effects in a variety of organisms. In addition to its direct cytotoxicity, Cd2+ acts as an immunomodulator at sub-toxic concentrations. Among other influences Cd2+ can induce inflammation, but the molecular basis for this effect is not well investigated. In this manuscript, we analyze the impact of Cd2+ on monocytes/macrophages, which are potent producers of pro-inflammatory cytokines, finding that Cd2+ treatment induced tumor necrosis factor (TNF)-α secretion. Based on the observation that another group IIb metal, zinc (Zn2+), has a physiological role in these events, we investigated if Cd2+ acts on the same molecular targets. Like Zn2+, Cd2+ inhibits phosphatases, and hereby dephosphorylation of mitogen activated protein kinases (MAPK). Consequently, treatment of cells with Cd2+ resulted in stimulation of ERK 1/2 and p38 MAPK phosphorylation. Furthermore, Cd2+-induced release of TNF-α from primary human monocytes was blocked by inhibitors for ERK 1/2 (U0126) and p38 MAPK (SB202190), demonstrating that MAPKs are involved in the induction of TNF-α by Cd2+.