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The Bcl10–Malt1 complex segregates FcRI-mediated nuclear factor B activation and cytokine production from mast cell degranulation

¹ Third Medical Department, Klinikum rechts der Isar and ² Institute for Medical Microbiology, Immunology, and Hygiene, Technical University of Munich, 81675 Munich, Germany
³ ZAUM-Center for Allergy and Environment, Technical University of Munich and Division of Environmental Dermatology and Allergy, GSF–National Research Center for Environment and Health, 80802 Munich, Germany
⁴ Institute of Clinical Molecular Biology and Tumor Genetics, GSF–National Research Center for Environment and Health, 81377 Munich, Germany
⁵ The Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario, M5G 2C1, Canada

CORRESPONDENCE Jürgen Ruland: jruland{at}lrz.tum.de

Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor FcRI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor B (NF-B) nor produce tumor necrosis factor or interleukin 6 upon FcRI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of FcRI-dependent mast cell activation that selectively uncouple NF-B–induced proinflammatory cytokine production from degranulation and leukotriene synthesis.

Abbreviations used: Bcl10, B cell lymphoma 10; BCR, B cell receptor; BMMC, bone marrow–derived mast cell; DNFB, dinitrofluorobenzene; DNP, dinitrophenyl; Erk, extracellular signal–regulated kinase; IB, inhibitor of B; IKK, IB kinase; Iono, ionomycin; Jnk, c-Jun NH2-terminal kinase; Malt1, mucosa-associated lymphoid tissue 1; MAP, mitogen-activated protein; PCA, passive cutaneous anaphylaxis; PKC, protein kinase C; SCF, stem cell factor.

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