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Silver Activates Calcium Signals in Rat Basophilic Leukemia-2H3 Mast Cells by a Mechanism That Differs from the FcRI-Activated Response¹

Yoshihiro Suzuki^2,*, Tetsuro Yoshimaru^*, Takashi Matsui^* and Chisei Ra

Departments of ^* Immunology and Microbiology and Molecular Cell Immunology and Allergology, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan

We previously showed that silver stimulates degranulation and leukotriene (LT) C₄ production in rat basophilic leukemia mast cells and now show that silver induces these events by a mechanism that differs from the FcRI-mediated response. In common with FcRI cross-linking, silver induced tyrosine phosphorylation of extracellular signal-regulated kinases and furthermore, PD98059, a specific inhibitor of extracellular signal-regulated kinase kinase dose-dependently inhibited the silver-induced LTC₄ production. In contrast to FcRI cross-linking, silver had no effect on the production of IL-4 and TNF-, indicating that different mechanisms are involved in the activation by these two stimuli. In line with this, silver had no or only marginal effect on the tyrosine phosphorylation of FcRI, Lyn, Syk, and linker for activation of T cells, the early and crucial events in FcRI signaling. Silver induced calcium signals that were involved in the metal-induced degranulation, but not LTC₄ production. Unlike Ag, the silver-induced calcium signals were resistant to the depletion of thapsigargin-sensitive calcium stores and the inhibition of tyrosine kinases and phospholipase C. These findings indicate that silver activates mast cells by bypassing the early signaling events required for the induction of calcium influx. Our data strongly suggest the existence of an alternative pathway bypassing the early signaling events in mast cell activation and indicate that silver may be useful for analyses of such alternative mechanisms.

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