title: PEST-domain-enriched tyrosine phosphatase and glucocorticoids as regulators of anaphylaxis in mice.
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 PLCγ1 phosphorylation and Ca(2+) 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 Ca(2+) 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.
authors: Karlsruhe Institute of Technology, Eggenstein-Leopoldshafen, Germany.
authors: D D
authors: DD
authors: Obiri
authors: N
authors: N
authors: Flink
authors: J V
authors: JV
authors: Maier
authors: A
authors: A
authors: Neeb
authors: D
authors: D
authors: Maddalo
authors: W
authors: W
authors: Thiele
authors: A
authors: A
authors: Menon
authors: M
authors: M
authors: Stassen
authors: R A
authors: RA
authors: Kulkarni
authors: M J
authors: MJ
authors: Garabedian
authors: A M
authors: AM
authors: Barrios
authors: A C B
authors: AC
authors: Cato
mesh_terms: D000707:Anaphylaxis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling; D015550:Cell Degranulation / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D007155:Immunologic Factors / Q000378:metabolism* / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051966:Phospholipase C gamma / Q000378:metabolism; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D007155:Immunologic Factors; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D051966:Phospholipase C gamma