title: AS252424, a PI3Kγ inhibitor, downregulates inflammatory responsiveness in mouse bone marrow-derived mast cells.
abstract: PI3Kγ is known to play an important role in inflammation and immune responses. Mast cells are closely involved in the initiation and regulation of immune responses and allergic inflammatory reactions. AS252424 is a specific PI3Kγ inhibitor. Until now, the anti-inflammatory effect of AS252424 on mast cells has not been reported. In this study, we investigated the anti-inflammatory effects of AS252424 on the inflammatory mediators in activated bone marrow-derived mast cells (BMMCs). AS252424 dramatically attenuated c-Kit ligand (KL)-induced leukotriene C4 (LTC4) generation and degranulation in BMMCs. Downregulating phosphorylation of cytosolic phospholipase A2 (cPLA2) and mitogen-activated protein kinase (MAPK) and inhibition of Ca(2+) liberation in BMMCs might be involved in the anti-inflammatory effects. These results suggested that AS252424 might be considered as a chemical tool or a drug candidate for prevention and therapy of inflammatory disease.
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Jin
authors.forename: Qianxiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Lee
authors.forename: Shingo
authors.initials: S
authors.lastname: Dan
authors.forename: Hong Quan
authors.initials: HQ
authors.lastname: Duan
authors.forename: Dexin
authors.initials: D
authors.lastname: Kong
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology; D007249:Inflammation / Q000188:drug therapy*; D008024:Ligands; D020935:MAP Kinase Signaling System; D008297:Male; D008407:Mast Cells / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054467:Phospholipases A2 / Q000378:metabolism; D010766:Phosphorylation; D045162:Thiazolidinediones / Q000494:pharmacology*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism
chemical_list: C512438:5-(5-(4-fluoro-2-hydroxyphenyl)furan-2-ylmethylene)thiazolidine-2,4-dione; D008024:Ligands; D000081082:Phosphoinositide-3 Kinase Inhibitors; D045162:Thiazolidinediones; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D054467:Phospholipases A2; D001619:beta-N-Acetylhexosaminidases; D002118:Calcium