FcεRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation

JEM © The Rockefeller University Press $8.00 Vol. 203, No. 2, February 20, 2006 337–347 www.jem.org/cgi/doi/10.1084/jem.20051982 337 Mast cells are derived from myeloid progenitor cells and widely distributed throughout vascularized tissues. They participate in innate and adaptive immune defenses against bacteria and parasites and play a key role in IgE-mediated allergic diseases such as atopy and asthma, which are responsible for increasing global health problems (1). Moreover, mast cells contribute to autoimmunity and are involved in pathological tissue remodeling processes that are associated with chronic infl ammation. All these biological and pathological functions are triggered by mast cell–derived proinfl ammatory mediators such as histamine, arachidonic acid metabolites, and cytokines, which are released upon mast cell activation. The major stimulus for mast cell activation is the aggregation of the high-affi nity receptor for IgE, FceRI (2, 3). Cross-linking of FceRIbound IgE with multivalent antigen or allergen triggers a series of biochemical events that culminate in mast cell eff ector function. Signaling is initiated through the phosphorylation of immunoreceptor tyrosine-based activation motifs in the tails of the FceRI β and γ subunits by Src family protein tyrosine kinases (2). The tyrosine-phosphorylated immunoreceptor tyrosine-based activation motifs recruit the kinase Syk, which, together with the activated receptor-proximal Src protein tyrosine kinases, mediates phosphorylation and consequent reorganization of adaptor and scaff olding proteins at the activated FceRI complex. Collectively, early signaling induces the activation of downstream enzymes such as phosphatidylinositol 3–kinase and phospholipase C, the generation 10.1084/jem.20051982 20051982 The Bcl10–Malt1 complex segregates FceRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation