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