Rcan 1 negatively regulates FcεRI-mediated signaling and mast cell function

Abstract

Aggregation of the high affinity IgE receptor (FceRI) activates a cascade of signaling events leading to mast cell activation. Subsequently, inhibitory signals are engaged for turning off activating signals. We identified that regulator of calcineurin (Rcan) 1 serves as a negative regulator for turning off FcεRI-mediated mast cell activation. FcεRI-induced Rcan1 expression was identified by suppression subtractive hybridization and verified by real-time quantitative polymerase chain reaction and Western blotting. Deficiency of Rcan1 led to increased calcineurin activity, increased nuclear factor of activated T cells and nuclear factor κB activation, increased cytokine production, and enhanced immunoglobulin E-mediated late-phase cutaneous reactions. Forced expression of Rcanl in wild-type or Rcan7-deficient mast cells reduced FceRI-mediated cytokine production. Rcanl deficiency also led to increased FcεRI-mediated mast cell degranulation and enhanced passive cutaneous anaphylaxis. Analysis of the Rcan 1 promoter identified a functional Egr 1 binding site. Biochemical and genetic evidence suggested that Egr 1 controls Rcanl expression. Our results identified Rcanl as a novel inhibitory signal in FcεRI-induced mast cell activation and established a new link of Egr1 and Rcan1 in FceRI signaling.