PEST-domain-enriched tyrosine phosphatase and glucocorticoids as regulators of anaphylaxis in mice
PEST-domain-enriched tyrosine phosphatase and glucocorticoids as regulators of anaphylaxis in mice
复制标题
DOI：
10.1111/j.1398-9995.2011.02731.x
复制
发表时间：
2012-02-01
期刊：
影响因子：
12.4
通讯作者：
Cato, A. C. B.
中科院分区：
文献类型：
--
作者：
Obiri, D. D.;Flink, N.;Cato, A. C. B.
背景：PEST结构域富集酪氨酸磷酸酶（PEP）是一种仅在造血细胞中表达的蛋白酪氨酸磷酸酶。它是T细胞受体信号传导的有效负调节剂，作用于受体偶联蛋白酪氨酸激酶。富含PEST结构域的酪氨酸磷酸酶也在肥大细胞中表达，并受糖皮质激素的正调控，但其功能尚不清楚。在本文中，分析了PEP在肥大细胞中的功能。研究方法：在PEP-/-和PEP+/+小鼠的骨髓源性肥大细胞（BMMC）中比较IgE受体交联后的信号转导级联。此外，在PEP+/+和PEP-/-小鼠中分析了抗原诱导的被动全身过敏反应（PSA）。结果：PEP-/-小鼠骨髓来源的肥大细胞表现出受损的PLC？1磷酸化和Ca 2+动员。此外，PEP缺陷的小鼠表现出受损的肥大细胞脱颗粒，对PSA较不敏感。用选择性抑制PEP活性的Au（I）膦络合物治疗野生型BMMC或小鼠，可导致Ca 2+信号通路缺陷，并减少过敏反应，类似于PEP基因缺失引起的过敏反应。糖皮质激素负性调节肥大细胞的广泛作用，增加PEP表达，仅部分抑制过敏反应。然而，糖皮质激素与PEP抑制剂联合使用时可有效抑制过敏反应。结论：富含PEST结构域的酪氨酸磷酸酶是过敏反应的重要正性调节因子。药理学抑制其活性与糖皮质激素给药一起提供了小鼠中PSA的有效拯救。
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.