Journal
TOXICOLOGICAL SCIENCES
Volume 118, Issue 1, Pages 108-118Publisher
OXFORD UNIV PRESS
DOI: 10.1093/toxsci/kfq256
Keywords
bone marrow; B cells; CaMKII; apoptosis; MAPK
Categories
Funding
- National Institutes of Health [P42 ES007381]
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Calcium is an essential signaling molecule in developing B cells, thus altering calcium dynamics represents a potential target for toxicant effects. GW7845, a tyrosine analog and potent peroxisome proliferator-activated receptor gamma agonist, induces rapid mitogen-activated protein kinase (MAPK)-dependent apoptosis in bone marrow B cells. Changes in calcium dynamics are capable of mediating rapid initiation of cell death; therefore, we investigated the contribution of calcium to GW7845-induced apoptosis. Treatment of a nontransformed murine pro/pre-B cell line (BU-11) with GW7845 (40 mu M) resulted in intracellular calcium release. Multiple features of GW7845-induced cell death were suppressed by the calcium chelator BAPTA, including MAPK activation, loss of mitochondrial membrane potential, cytochrome c release, caspase-3 activation, and DNA fragmentation. A likely mechanism for the calcium-mediated effects is activation of CaMKII, a calcium-dependent MAP4K. We observed that three CaMKII isoforms (beta, gamma, and delta) are expressed in lymphoid tissues and bone marrow B cells. Treatment with GW7845 increased CaMKII activity. All features of GW7845-induced cell death, except loss of mitochondrial membrane potential, were suppressed by CaMKII inhibitors (KN93 and AIP-II), suggesting the activation of multiple calcium-driven pathways. To determine if CaMKII activation is a common feature of early B cell death following perturbation of Ca(2+) flux, we dissected tributyltin (TBT)-induced death signaling. High-dose TBT (1 mu M) is known to activate calcium-dependent death. TBT induced rapid apoptosis that was associated with intracellular calcium release, CaMKII activation and MAPK activation, and was inhibited by AIP-II. Thus, we show that early B cells are susceptible to calcium-triggered cell death through a CaMKII/MAPK-dependent pathway.
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