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