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Targeting sphingosine‐1‐phosphate receptors regulates in vitro and in vivo mast cell functions
Author(s) -
OSKERITZIAN Carole Anna,
Price Megan M,
Kennedy Sarah,
Ryan John J,
Spiegel Sarah
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.484
Subject(s) - sphingosine 1 phosphate , degranulation , tryptase , sphingosine 1 phosphate receptor , in vivo , histamine , receptor , chemokine , sphingosine , immunoglobulin e , lipid signaling , chemistry , mast cell , receptor antagonist , immunology , microbiology and biotechnology , antagonist , pharmacology , biology , biochemistry , antibody
Sphingosine‐1‐phosphate (S1P), a bioactive lipid mediator, is produced and secreted by mast cells (MC). We previously showed that S1P potently induces degranulation of cord blood‐derived, tryptase + MC and secretion of cytokines and chemokine. We have now established that S1P also triggers activation of skin‐derived, chymase + tryptase + MC (Sk‐MC) and stimulates their migration. To examine the role of S1P and the two S1P receptor (R) subtypes expressed by MC, S1P 1 and S1P 2 , in regulating their activation and motility, we utilized JTE‐013, a S1P 2 antagonist, and VPC23019, a S1P 1 antagonist. Blockade of S1P 2 by pretreatment of MC with JTE‐013 significantly decreased IgE/antigen (Ag) ‐ and S1P‐ dependent degranulation, and secretion of IL‐6, TNF‐α and MCP‐1 from LAD2 and Sk‐MC. These results suggest that IgE/Ag‐induced activation involves inside‐out signaling by S1P and transactivation of S1P 2 . In agreement, VPC23019 abolished migratory responses of hMC induced by both Ag and S1P. Importantly, pretreatment of mice with JTE‐013 prior to Ag challenge significantly inhibited MC‐dependent passive systemic anaphylaxis, as assessed by effects on body temperature and histamine, substantiating the importance of activation of the S1P 2 R on MC in vivo. These results pave new avenues for therapeutic strategies in MC‐dependent diseases, such as allergies and asthma. Supported by NIH KO1 AR053186 to CAO and RO1 AI50094 to SS.