Rcan1 negatively regulates Fc epsilonRI-mediated signaling and mast cell function.
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.
Yang
Yong Jun
YJ
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.
Chen
Wei
W
Edgar
Alexander
A
Li
Bo
B
Molkentin
Jeffery D
JD
Berman
Jason N
JN
Lin
Tong-Jun
TJ
D000818:Animals; D015153:Blotting, Western; D002135:Calcium-Binding Proteins; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000276:immunology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006967:Hypersensitivity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008407:Mast Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011940:Receptor Aggregation / Q000502:physiology; D017455:Receptors, IgE / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012710:Serum Albumin, Bovine / Q000276:immunology; D015398:Signal Transduction / Q000502:physiology*
D002135:Calcium-Binding Proteins; D016207:Cytokines; C511512:DSCR1 protein, mouse; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D017455:Receptors, IgE; C038601:trinitrophenyl-bovine serum albumin; D012710:Serum Albumin, Bovine; D004139:Dinitrofluorobenzene; D020928:Mitogen-Activated Protein Kinases