The Bcl10-Malt1 complex segregates FcεRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation

Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor Fc epsilon RI, 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 mucos-aassociated 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 kappa B (NF-kappa B) nor produce tumor necrosis factor.. or interleukin 6 upon Fc epsilon RI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of Fc epsilon RI-dependent mast cell activation that selectively uncouple NF-kappa B-induced proinflammatory cytokine production from degranulation and leukotriene synthesis.