Silver activates mast cells through reactive oxygen species production and a thiol-sensitive store-independent Ca2+ influx.

In genetically susceptible human and/or experimental animals, heavy metals such as mercury, gold, and silver have been shown to highly induce adverse immunological reactions such as allergy and autoimmunity, in which mast cell degranulation is implicated as playing a role. We previously reported that silver activates mast cells and induces Ca2+ influx without stimulating intracellular signaling events required for activation of store-operated Ca2+ channels (SOCs). The purpose of the present study was to elucidate the possible involvement of reactive oxygen species (ROS) in the biological effects of silver. Analysis using oxidant-sensitive fluorescent probes such as dichlorodihydrofluorescein and scopoletin, as well as MCLA-amplified chemiluminescence, showed that silver induced intracellular production and/or extracellular release of ROS. Silver induced mast cell degranulation in a Ca2+ -dependent manner. Unlike IgE antigen, silver-induced Ca2+ influx was not affected by depletion of internal Ca2+ stores. Instead, the metal-induced Ca2+ influx was abolished and reversed by the cell-impermeant thiol-reducing agent dithiothreitol, indicating the regulation by oxidation of vicinal thiols on the cell surface. Consistent with this view, Ca2+ influx was blocked by the glutathione peroxidase mimetic ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) and the superoxide dismutase mimetic manganese(III) tetrakis 4-(benzoic acid)porphyrin, but not by exogenously added catalase or superoxide dismutase. These findings indicate that silver evokes the release of ROS and oxidation of thiols critical for the activation of a Ca2+ channel other than SOC. Such a novel ROS-dependent pathway might play a role in mast cell degranulation in metal-induced allergic and autoimmune reactions.