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* Deutsches Krebsforschungszentrum Heidelberg, Division of Signal Transduction and Growth Control (A100), Heidelberg, Germany;
Leibniz-Institut für Altersforschung Fritz-Lipmann-Institut, Division of Molecular Biology of Tissue-Specific Hormone Action, Jena, Germany;
Institute of Physiological Chemistry, Dresden University of Technology, Dresden, Germany; and
Hebrew University Hadassah Medical School, Department of Biochemistry, Jerusalem, Israel
Mast cells are effector cells of IgE-mediated immune responses frequently found at the vicinity of blood vessels, the margins of diverse tumors and at sites of potential infection and inflammation. Upon IgE-mediated stimulation, mast cells produce and secrete a broad spectrum of cytokines and other inflammatory mediators. Recent work identified JunB, a member of the AP-1 transcription factor family, as critical regulator of basal and induced expression of inflammatory mediators in fibroblasts and T cells. To study the impact of JunB on mast cell biology, we analyzed JunB-deficient mast cells. Mast cells lacking JunB display a normal in vivo maturation, and JunB-deficient bone marrow cells in vitro differentiated to mast cells show no alterations in proliferation or apoptosis. But these cells exhibit impaired IgE-mediated degranulation most likely due to diminished expression of SWAP-70, Synaptotagmin-1, and VAMP-8, and due to impaired influx of extracellular calcium. Moreover, JunB-deficient bone marrow mast cells display an altered cytokine expression profile in response to IgE stimulation. In line with these findings, the contribution of JunB-deficient mast cells to angiogenesis, as analyzed in an in vitro tube formation assay on matrigel, is severely impaired due to limiting amounts of synthesized and secreted vascular endothelial growth factor. Thus, JunB is a critical regulator of intrinsic mast cell functions including cross-talk with endothelial cells.
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1 This work was supported by Training and Mobility of Researchers Programs of the European Economic Community, the Deutsche Forschungsgemeinschaft (Scho 365/3-2 and SFB-TR23, Tu-220/3), and the German-Israelian Foundation for Scientific Research and Development (1-726-10.2/2002).
2 M.S.-K. and B.H. contributed equally to this work.
3 Address correspondence and reprint requests Dr. Marina Schorpp-Kistner, Deutsches Krebsforschungszentrum Heidelberg, Division of Signal Transduction and Growth Control (A100), Im Neuenheimer Feld 280, Heidelberg, Germany. E-mail address: marina.schorpp{at}dkfz-heidelberg.de
4 Abbreviations used in this paper: SYT, synaptotagmin; SNARE, soluble NSF attachment receptor; VAMP, vehicle-associated membrane protein; SNAP, synaptosome-associated protein; STX, syntaxin; BMMC, bone marrow-derived mast cell; VEGF, vascular endothelial growth factor.
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