Concurrent inhibition of kit- and FcepsilonRI-mediated signaling: coordinated suppression of mast cell activation.

  • Jensen B
  • Beaven M
  • Iwaki S
 et al. 
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Abstract

Although primarily required for the growth, differentiation, and survival of mast cells, Kit ligand (stem cell factor) is also required for optimal antigen-mediated mast cell activation. Therefore, concurrent inhibition of Kit- and FcepsilonRI-mediated signaling would be an attractive approach for targeting mast cell-driven allergic reactions. To explore this concept, we examined the effects of hypothemycin, a molecule that we identified as having such properties, in human and mouse mast cells. Hypothemycin blocked Kit activation and Kit-mediated mast cell adhesion in a similar manner to the well characterized Kit inhibitor imatinib mesylate (imatinib). In contrast to imatinib, however, hypothemycin also effectively inhibited FcepsilonRI-mediated degranulation and cytokine production in addition to the potentiation of these responses via Kit. The effect of hypothemycin on Kit-mediated responses could be explained by its inhibition of Kit kinase activity, whereas the inhibitory effects on FcepsilonRI-dependent signaling were at the level of Btk activation. Because hypothemycin also significantly reduced the mouse passive cutaneous anaphylaxis response in vivo, these data provide proof of principle for a coordinated approach for the suppression of mast cell activation and provide a rationale for the development of compounds with a similar therapeutic profile.

Author-supplied keywords

  • Anaphylaxis
  • Anaphylaxis: chemically induced
  • Anaphylaxis: immunology
  • Anaphylaxis: prevention & control
  • Animals
  • Benzamides
  • Calcium
  • Calcium: immunology
  • Cell Degranulation
  • Cell Degranulation: drug effects
  • Cells, Cultured
  • Cytokines
  • Cytokines: immunology
  • Humans
  • Imatinib Mesylate
  • Immunoglobulin E
  • Immunoglobulin E: immunology
  • Mast Cells
  • Mast Cells: drug effects
  • Mast Cells: physiology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Piperazines
  • Piperazines: pharmacology
  • Pyrimidines
  • Pyrimidines: pharmacology
  • Receptors, IgE
  • Receptors, IgE: antagonists & inhibitors
  • Receptors, IgE: immunology
  • Stem Cell Factor
  • Stem Cell Factor: antagonists & inhibitors
  • Stem Cell Factor: immunology
  • Zearalenone
  • Zearalenone: analogs & derivatives
  • Zearalenone: pharmacology

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Authors

  • Bettina M Jensen

  • Michael A Beaven

  • Shoko Iwaki

  • Dean D Metcalfe

  • Alasdair M Gilfillan

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