Extracellular signal-regulated kinase-signaling-dependent G2/M arrest and cell death in murine macrophages by cadmium.
Cadmium is a nonessential heavy metal and a well-known persistent environmental pollutant. It causes a variety of toxic effects, including immunotoxicity. The exact mechanism of its cellular effects still is unclear. Cell-cycle regulation is an important factor that modulates cell death; however, cadmium-mediated cell-cycle arrest leading to cell death in murine macrophages has not been investigated. Cadmium at 20 microM induced both apoptotic and necrotic death in murine macrophage (J774A.1) cultures at 24 h. Cadmium at 20 microM triggered re-entry of G0/G1 to the next phase and increased the number of cells in the G2/M phase at 24 h. Phosphorylation of extracellular signal-regulated kinase (ERK) correlated with the cyclin-dependent kinase inhibitor p21WAF1/CIP1 induction. Inhibition of ERK activation by PD98059 resulted in G0/G1 arrest and partially released the cadmium-mediated G2/M arrest. Inhibition of ERK phosphorylation by PD98059 strongly attenuated cadmium-induced necrotic cell death, but did not prevent caspase-3 activation and DNA fragmentation. Necrosis rather than apoptosis was caused by cadmium-induced ERK signaling in J774A.1 cells. A scavenger of reactive oxygen species (ROS), N-acetylcystein, decreased cadmium-induced ERK activation and necrotic cell death, suggesting that cadmium induces the ROS-ERK-p21WAF1/CIP1 signaling pathway, leading to G2/M arrest and cell death. These findings may be important in further understanding the cellular mechanisms of cadmium toxicity to provide information to assess objectively risk for this metal.
Kim
Jiyoung
J
Interdisciplinary Program in Toxicology, Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens 30602, USA.
Kim
Sang Hyun
SH
Johnson
Victor J
VJ
Sharma
Raghubir P
RP
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D002104:Cadmium / Q000633:toxicity*; D019256:Cadmium Chloride / Q000633:toxicity; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016195:G2 Phase / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors
D050759:Cyclin-Dependent Kinase Inhibitor p21; D017382:Reactive Oxygen Species; D002104:Cadmium; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D019256:Cadmium Chloride; D000111:Acetylcysteine