Rcan1 negatively regulates Fc epsilonRI-mediated signaling and mast cell function

J Exp Med. 2009 Jan 16;206(1):195-207. doi: 10.1084/jem.20081140. Epub 2009 Jan 5.

Abstract

Aggregation of the high affinity IgE receptor (Fc epsilonRI) 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 Fc epsilonRI-mediated mast cell activation. Fc epsilonRI-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 kappaB activation, increased cytokine production, and enhanced immunoglobulin E-mediated late-phase cutaneous reactions. Forced expression of Rcan1 in wild-type or Rcan1-deficient mast cells reduced Fc epsilonRI-mediated cytokine production. Rcan1 deficiency also led to increased Fc epsilonRI-mediated mast cell degranulation and enhanced passive cutaneous anaphylaxis. Analysis of the Rcan1 promoter identified a functional Egr1 binding site. Biochemical and genetic evidence suggested that Egr1 controls Rcan1 expression. Our results identified Rcan1 as a novel inhibitory signal in Fc epsilonRI-induced mast cell activation and established a new link of Egr1 and Rcan1 in Fc epsilonRI signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium-Binding Proteins
  • Cell Degranulation / genetics
  • Cell Degranulation / immunology
  • Cells, Cultured
  • Chromatin Immunoprecipitation
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dinitrofluorobenzene / immunology
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Gene Expression
  • Hypersensitivity / genetics
  • Hypersensitivity / metabolism
  • Hypersensitivity / pathology
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mast Cells / cytology
  • Mast Cells / metabolism
  • Mast Cells / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitogen-Activated Protein Kinases / metabolism
  • Muscle Proteins / deficiency
  • Muscle Proteins / genetics
  • Muscle Proteins / physiology*
  • NF-kappa B / metabolism
  • NFATC Transcription Factors / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Binding
  • Receptor Aggregation / physiology
  • Receptors, IgE / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serum Albumin, Bovine / immunology
  • Signal Transduction / physiology*

Substances

  • Calcium-Binding Proteins
  • Cytokines
  • DSCR1 protein, mouse
  • Early Growth Response Protein 1
  • Egr1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • NF-kappa B
  • NFATC Transcription Factors
  • Receptors, IgE
  • trinitrophenyl-bovine serum albumin
  • Serum Albumin, Bovine
  • Dinitrofluorobenzene
  • Mitogen-Activated Protein Kinases