Analysis of Two Major Intracellular Phospholipases A2 (PLA2) in Mast Cells Reveals Crucial Contribution of Cytosolic PLA2α, Not Ca2+-independent PLA2β, to Lipid Mobilization in Proximal Mast Cells and Distal Fibroblasts
Analysis of Two Major Intracellular Phospholipases A2 (PLA2) in Mast Cells Reveals Crucial Contribution of Cytosolic PLA2α, Not Ca2+-independent PLA2β, to Lipid Mobilization in Proximal Mast Cells and Distal Fibroblasts
复制标题
DOI：
10.1074/jbc.m111.290312
复制
发表时间：
2011-10-28
影响因子：
4.8
通讯作者：
Murakamia, Makoto
中科院分区：
文献类型：
--
作者：
Ueno, Noriko;Taketomi, Yoshitaka;Murakamia, Makoto
肥大细胞释放多种介质，包括花生四烯酸（AA）代谢产物，以调节过敏，炎症和宿主防御，其在血管外微环境中的分化和成熟取决于基质细胞因子干细胞因子。小鼠肥大细胞表达两种主要的细胞内磷脂酶A（2）（PLA（2）s），即IVA型胞质PLA（2）（cPLA（2）α）和VIA型Ca 2+非依赖性PLA 2（iPLA（2）β），cPLA（2）α在肥大细胞合成类花生酸中的作用已得到充分证明。对缺乏cPLA（2）α（Pla 2g 4a（-/-））或iPLA（2）β（Pla 2g 6（-/-））的小鼠骨髓源性肥大细胞（BMMC）进行的脂质组学分析显示，在Fc β RI介导的活化过程中，甚至在成纤维细胞依赖性成熟过程中，具有AA的磷脂被cPLA（2）α而不是iPLA（2）β选择性水解。在Pla 2g 6（-/-）BMMC中，Fc β RI依赖性效应子功能和成熟驱动的磷脂重塑均未受损。虽然BMMC不产生前列腺素E-2（PGE（2）），但在共培养的成纤维细胞中，由cPLA（2）alpha在成熟过程中从BMMC释放的AA被微粒体PGE合酶-1（mPGES-1）转化为PGE（2），因此，在体外和体内，Pla 2g 4a（-/-）BMMC促进微环境PGE（2）合成的效率低于野生型BMMC。mPGES-1（Ptges（-/-））缺陷小鼠的局部过敏反应增强。这些结果表明，肥大细胞中的cPLA（2）α通过AA转移机制与基质mPGES-1功能性偶联，以提供抗过敏性PGE（2）。虽然iPLA（2）beta部分负责巨噬细胞和树突状细胞产生PGE（2），但它对肥大细胞的成熟和功能至关重要。
Mast cells release a variety of mediators, including arachidonic acid (AA) metabolites, to regulate allergy, inflammation, and host defense, and their differentiation and maturation within extravascular microenvironments depend on the stromal cytokine stem cell factor. Mouse mast cells express two major intracellular phospholipases A(2) (PLA(2)s), namely group IVA cytosolic PLA(2) (cPLA(2)alpha) and group VIA Ca2+-independent PLA2 (iPLA(2)beta), and the role of cPLA(2)alpha in eicosanoid synthesis by mast cells has been well documented. Lipidomic analyses of mouse bone marrow-derived mast cells (BMMCs) lacking cPLA(2)alpha (Pla2g4a(-/-)) or iPLA(2)beta (Pla2g6(-/-)) revealed that phospholipids with AA were selectively hydrolyzed by cPLA(2)alpha, not by iPLA(2)beta, during Fc epsilon RI-mediated activation and even during fibroblast-dependent maturation. Neither Fc epsilon RI-dependent effector functions nor maturation-driven phospholipid remodeling was impaired in Pla2g6(-/-) BMMCs. Although BMMCs did not produce prostaglandin E-2 (PGE(2)), the AA released by cPLA(2)alpha from BMMCs during maturation was converted to PGE(2) by microsomal PGE synthase-1 (mPGES-1) in cocultured fibroblasts, and accordingly, Pla2g4a(-/-) BMMCs promoted microenvironmental PGE(2) synthesis less efficiently than wild-type BMMCs both in vitro and in vivo. Mice deficient in mPGES-1 (Ptges(-/-)) had an augmented local anaphylactic response. These results suggest that cPLA(2)alpha in mast cells is functionally coupled, through the AA transfer mechanism, with stromal mPGES-1 to provide anti-anaphylactic PGE(2). Although iPLA(2)beta is partially responsible for PGE(2) production by macrophages and dendritic cells, it is dispensable for mast cell maturation and function.