Silver activates calcium signals in rat basophilic leukemia-2H3 mast cells by a mechanism that differs from the Fc epsilon RI-activated response.
We previously showed that silver stimulates degranulation and leukotriene (LT) C(4) production in rat basophilic leukemia mast cells and now show that silver induces these events by a mechanism that differs from the FcepsilonRI-mediated response. In common with FcepsilonRI 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 LTC(4) production. In contrast to FcepsilonRI cross-linking, silver had no effect on the production of IL-4 and TNF-alpha, 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 FcepsilonRIbeta, Lyn, Syk, and linker for activation of T cells, the early and crucial events in FcepsilonRI signaling. Silver induced calcium signals that were involved in the metal-induced degranulation, but not LTC(4) 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 Cgamma. 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.
Suzuki
Yoshihiro
Y
Department of Immunology and Microbiology, Advanced Medical Research Center, Nihon University School of Medicine, Tokyo, Japan. ysuzuki@med.nihon-u.ac.jp
Yoshimaru
Tetsuro
T
Matsui
Takashi
T
Ra
Chisei
C
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects* / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D004792:Enzyme Precursors / Q000378:metabolism; D007113:Immunity, Innate; D015847:Interleukin-4 / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D015471:Leukemia, Basophilic, Acute; D017997:Leukotriene C4 / Q000096:biosynthesis; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017455:Receptors, IgE / Q000502:physiology*; D012834:Silver / Q000494:pharmacology; D012835:Silver Nitrate / Q000494:pharmacology; D000072377:Syk Kinase; D019284:Thapsigargin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D002352:Carrier Proteins; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D010750:Phosphoproteins; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D017997:Leukotriene C4; D012834:Silver; D014443:Tyrosine; D019284:Thapsigargin; D012835:Silver Nitrate; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606898:Syk protein, rat; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D002118:Calcium