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 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.
Footnotes
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This work was supported by the NIAID and National Heart, Lung, and Blood Institute Intramural Programs of the National Institutes of Health.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.125237.
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ABBREVIATIONS: IgE, immunoglobulin E; FcϵRI, high-affinity receptor for IgE; SCF, stem cell factor; LAT, linker for activation of T cells; PL, phospholipase; PI3K, phosphoinositide 3-kinase; HuMC, human mast cell; NIAID, National Institute of Allergy and Infectious Diseases; IL, interleukin; BMMC, mouse bone marrow-derived mast cell; NIH, National Institutes of Health; BSA, bovine serum albumin; DNP, dinitrophenyl; HSA, human serum albumin; p, phospho; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH2-terminal kinase; NF, nuclear factor; PBS, phosphate-buffered saline; DMSO, dimethyl sulfoxide; GM-CSF, granulocyte macrophage colony-stimulating factor; TNF, tumor necrosis factor; MAP, mitogen-activated protein; Ag, antigen; Hypo, hypothemycin.
- Received May 3, 2007.
- Accepted October 4, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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