Received for publication May 4, 2007.
Revised October 2, 2007.
Accepted for publication October 4, 2007.

Concurrent inhibition of Kit- and FcRI-mediated signaling: Coordinated suppression of mast cell activation

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 FcRI-mediated signaling would be an attractive approach for targeting mast cell-driven allergic inflammation. To explore this concept, we examined the effects of hypothemycin, a molecule which 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 FcRI-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 FcRI-dependent signaling was at the level of Btk activation. As 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 provides a rationale for the development of compounds with a similar therapeutic profile.

Key words: FcRI, Kit, Stem cell factor, allergy, mast cells, tyrosine kinase inhibitor