The Journal of Experimental Medicine
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Published online January 5, 2009
doi:10.1084/jem.20081140
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2009 Yang et al.
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ARTICLE

 Rcan1 negatively regulates Fc{epsilon}RI-mediated signaling and mast cell function

Yong Jun Yang1, Wei Chen1, Alexander Edgar1, Bo Li2, Jeffery D. Molkentin3, Jason N. Berman1, and Tong-Jun Lin1

1 Department of Microbiology and Immunology and Department of Pediatrics, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada
2 Department of Immunology, Capital Medical University, Beijing 100069, China
3 Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OH 45229

CORRESPONDENCE Tong-Jun Lin: tong-jun.lin{at}dal.ca

Aggregation of the high affinity IgE receptor (Fc{epsilon}RI) 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{epsilon}RI-mediated mast cell activation. Fc{epsilon}RI-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 {kappa}B 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{epsilon}RI-mediated cytokine production. Rcan1 deficiency also led to increased Fc{epsilon}RI-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{epsilon}RI-induced mast cell activation and established a new link of Egr1 and Rcan1 in Fc{epsilon}RI signaling.

Abbreviations used: BMMC, bone marrow–derived mast cell; ChIP, chromatin immunoprecipitation; DNFB, dinitrofluorobenzene; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3 kinase; Rcan, regulator of calcineurin; SSH, suppression subtractive hybridization.

© 2009 Yang et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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