title: Analysis of two major intracellular phospholipases A(2) (PLA(2)) in mast cells reveals crucial contribution of cytosolic PLA(2)α, not Ca(2+)-independent PLA(2)β, to lipid mobilization in proximal mast cells and distal fibroblasts.
abstract: 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)α) and group VIA Ca(2+)-independent PLA(2) (iPLA(2)β), and the role of cPLA(2)α in eicosanoid synthesis by mast cells has been well documented. Lipidomic analyses of mouse bone marrow-derived mast cells (BMMCs) lacking cPLA(2)α (Pla2g4a(-/-)) or iPLA(2)β (Pla2g6(-/-)) revealed that phospholipids with AA were selectively hydrolyzed by cPLA(2)α, not by iPLA(2)β, during FcεRI-mediated activation and even during fibroblast-dependent maturation. Neither FcεRI-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)α 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)α in mast cells is functionally coupled, through the AA transfer mechanism, with stromal mPGES-1 to provide anti-anaphylactic PGE(2). Although iPLA(2)β is partially responsible for PGE(2) production by macrophages and dendritic cells, it is dispensable for mast cell maturation and function.
authors: Lipid Metabolism Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 256-8506, Japan.
authors: Noriko
authors: N
authors: Ueno
authors: Yoshitaka
authors: Y
authors: Taketomi
authors: Kei
authors: K
authors: Yamamoto
authors: Tetsuya
authors: T
authors: Hirabayashi
authors: Daisuke
authors: D
authors: Kamei
authors: Yoshihiro
authors: Y
authors: Kita
authors: Takao
authors: T
authors: Shimizu
authors: Koei
authors: K
authors: Shinzawa
authors: Yoshihide
authors: Y
authors: Tsujimoto
authors: Kazutaka
authors: K
authors: Ikeda
authors: Ryo
authors: R
authors: Taguchi
authors: Makoto
authors: M
authors: Murakami
mesh_terms: D000707:Anaphylaxis / Q000201:enzymology / Q000235:genetics; D000818:Animals; D016718:Arachidonic Acid / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000201:enzymology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D015232:Dinoprostone / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology*; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D054522:Group VI Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases
chemical_list: D010743:Phospholipids; D016718:Arachidonic Acid; D054513:Group IV Phospholipases A2; D054522:Group VI Phospholipases A2; C516476:Pla2g6 protein, mouse; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone