Impact of lead and mercuric ions on the interleukin-2-dependent proliferation and survival of T cells.
Mercury and lead are widespread in the environment, causing chronic exposure of a large population to low concentrations of these metals. While several studies demonstrated that low levels of both metals affect the immune system, little is known about underlying molecular mechanisms. The objective of this study was to investigate the impact of mercuric (Hg(2+)) and lead (Pb(2+)) ions on T cells. Up to 100 μM Pb(NO(3))(2) had no effect on cellular viability and proliferation. In contrast, HgCl(2) caused a concentration-dependent decline of viable leukocytes and especially of activated T cells. Additionally, Hg(2+) induced reactive oxygen species (ROS) generation accompanied by the loss of mitochondrial transmembrane potential, measured by Dihydrorhodamine and Rhodamine-123, respectively. The antioxidant N-acetylcysteine partially reversed the toxic effects of Hg(2+), pointing to an involvement of ROS. The major cytokine controlling T-cell survival and proliferation is interleukin (IL)-2. Hg(2+) had no effect on the secretion of IL-2, but on IL-2 mediated signal transduction pathways, reducing phosphorylation of the downstream kinases ERK1/2 and AKT. Moreover, Hg(2+) led to an arrest of the cells in the S phase of the cell cycle. Taken together, these data fit a model in which Hg(2+) disrupts mitochondria, and the resulting release of ROS inhibits IL-2-dependent signal transduction, reducing proliferation and survival of T cells.
Institute of Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
Andrea
A
Jorissen
Laura M
LM
Plum
Lothar
L
Rink
Hajo
H
Haase
D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism*; D007477:Ions; D007854:Lead / Q000633:toxicity*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008627:Mercuric Chloride / Q000633:toxicity*; D009566:Nitrates / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D016196:S Phase / Q000187:drug effects; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D015415:Biomarkers; D007376:Interleukin-2; D007477:Ions; D009566:Nitrates; D017382:Reactive Oxygen Species; D007854:Lead; D008627:Mercuric Chloride; C017461:lead nitrate