PT - JOURNAL ARTICLE AU - Bettina M. Jensen AU - Michael A. Beaven AU - Shoko Iwaki AU - Dean D. Metcalfe AU - Alasdair M. Gilfillan TI - Concurrent Inhibition of Kit- and FcϵRI-Mediated Signaling: Coordinated Suppression of Mast Cell Activation AID - 10.1124/jpet.107.125237 DP - 2008 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 128--138 VI - 324 IP - 1 4099 - http://jpet.aspetjournals.org/content/324/1/128.short 4100 - http://jpet.aspetjournals.org/content/324/1/128.full SO - J Pharmacol Exp Ther2008 Jan 01; 324 AB - 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 FcϵRI-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 FcϵRI-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 FcϵRI-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. The American Society for Pharmacology and Experimental Therapeutics