Published online before print April 28, 2009

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1108691

Received for publication November 14, 2008.
Revised February 23, 2009.
Accepted for publication March 9, 2009.

Article

Ca²⁺-dependent mast cell death induced by Ag (I) via cardiolipin oxidation and ATP depletion

Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Science, Tokyo, Japan

^@ To whom correspondence should be addressed. E-mail: ysuzuki{at}med.nihon-u.ac.jp.

Abstract

In genetically susceptible humans and/or experimental animals, ions of heavy metals, Hg (II), Au (III), and Ag (I) have been shown to strongly induce autoimmunity, in which mast cells have been implicated to play a role. Here, we demonstrate that Ag (I) application results in mast cell death through a unique Ca²⁺- and mitochondria-dependent pathway. As cellular susceptibilities to Ag (I) cytotoxicity varied considerably, we analyzed the cell death pathway in the low and high responding cells. In the low responding cells, long application (e.g., 20 h) of Ag (I) at concentrations (30 µM) induced cell death, which was accompanied by mitochondrial membrane depolarization, cyt c release, and caspase-3/7 activation but was not prevented by selective inhibitors of caspase-3/7 and the mitochondrial permeability transition. The cell death was preceded by elevations in the cytoplasmic and mitochondrial Ca²⁺ levels, and Ca²⁺ responses and cell death were prevented by thiol reagents, including DTT, N-acetylcysteine, and reduced glutathione monoethyl ester. In the high responding cells, Ag (I) evoked considerable cell death by necrosis within 1 h, without inducing caspase activation, and this cell death was reduced significantly by depleting extracellular but not intracellular Ca²⁺. Moreover, Ag (I) strongly induced Ca²⁺-dependent CL oxidation and intracellular ATP depletion, both of which were blocked by thiol reagents. These results suggest that Ag (I) activates thiol-dependent Ca²⁺ channels, thereby promoting Ca²⁺-dependent CL oxidation, cyt c release, and ATP depletion. This necrotic cell death may play roles in Ag-induced inflammation and autoimmune disorders.

Key Words: silver • autoimmune • adaptive immunity

This article has been cited by other articles:

				T. Inoue, Y. Suzuki, T. Yoshimaru, and C. Ra Nitric oxide positively regulates Ag (I)-induced Ca2+ influx and mast cell activation: role of a nitric oxide synthase-independent pathway J. Leukoc. Biol., December 1, 2009; 86(6): 1365 - 1375. [Abstract] [Full Text] [PDF]