PEST-domain-enriched tyrosine phosphatase and glucocorticoids as regulators of anaphylaxis in mice

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Author list: Obiri DD, Flink N, Maier JV, Neeb A, Maddalo D, Thiele W, Menon A, Stassen M, Kulkarni RA, Garabedian MJ, Barrios AM, Cato ACB
Publisher: Wiley: 12 months
Publication year: 2012
Volume number: 67
Issue number: 2
Start page: 175
End page: 182
Number of pages: 8
ISSN: 0105-4538
Languages: English-Great Britain (EN-GB)


Abstract

Background: PEST-domain-enriched tyrosine phosphatase (PEP) is a protein tyrosine phosphatase exclusively expressed in hematopoietic cells. It is a potent negative regulator of T-cell receptor signalling that acts on receptor-coupled protein tyrosine kinases. PEST-domain-enriched tyrosine phosphatase is also expressed in mast cell and is positively regulated by glucocorticoids, but its function is unknown. In this communication, the function of PEP is analysed in mast cells. Methods: Signal transduction cascades following IgE receptor cross-linking were compared in bone marrow-derived mast cells (BMMC) from PEP-/- and PEP+/+ mice. Furthermore, antigen-induced passive systemic anaphylaxis (PSA) was analysed in PEP+/+ and PEP-/- mice. Results: Bone marrow-derived mast cells from PEP-/- mice showed impaired PLC?1 phosphorylation and Ca2+ mobilization. Additionally, mice deficient in PEP showed impaired mast cell degranulation and were less susceptible to PSA. Treatment of wild-type BMMC or mice with an Au(I)phosphine complex that selectively inhibits PEP activity produced defects in Ca2+ signalling pathway and reduced anaphylaxis similar to that caused by the deletion of the PEP gene. Glucocorticoid that negatively regulates a wide range of mast cell action increased PEP expression and only partially inhibited anaphylaxis. However, glucocorticoid potently inhibited anaphylaxis when combined with the PEP inhibitor. Conclusions: PEST-domain-enriched tyrosine phosphatase is an important positive regulator of anaphylaxis. Pharmacological inhibition of its activity together with glucocorticoid administration provide an effective rescue for PSA in mice.


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Last updated on 2019-23-08 at 11:15