title: Concurrent inhibition of kit- and FcepsilonRI-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 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.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11C206, 10 Center Drive, MSC 1881, Bethesda, MD 20892-1881, USA.
authors.forename: Bettina M
authors.initials: BM
authors.lastname: Jensen
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Shoko
authors.initials: S
authors.lastname: Iwaki
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
mesh_terms: D000707:Anaphylaxis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control; D000818:Animals; D001549:Benzamides; D002118:Calcium / Q000276:immunology; D015550:Cell Degranulation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D017455:Receptors, IgE / Q000037:antagonists & inhibitors / Q000276:immunology*; D019089:Stem Cell Factor / Q000037:antagonists & inhibitors / Q000276:immunology*; D015025:Zearalenone / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001549:Benzamides; D016207:Cytokines; D010879:Piperazines; D011743:Pyrimidines; D017455:Receptors, IgE; D019089:Stem Cell Factor; C120440:hypothemycin; D007073:Immunoglobulin E; D015025:Zearalenone; D000068877:Imatinib Mesylate; D002118:Calcium