Cadmium ions induce monocytic production of tumor necrosis factor-alpha by inhibiting mitogen activated protein kinase dephosphorylation.
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+).
Haase
Hajo
H
Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Ober-Blöbaum
Julia L
JL
Engelhardt
Gabriela
G
Hebel
Silke
S
Rink
Lothar
L
D000818:Animals; D015153:Blotting, Western; D002104:Cadmium / Q000633:toxicity*; D002460:Cell Line; D004785:Environmental Pollutants / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D002104:Cadmium; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases