期刊
EXPERIMENTAL CELL RESEARCH
卷 318, 期 4, 页码 350-360出版社
ELSEVIER INC
DOI: 10.1016/j.yexcr.2011.11.013
关键词
Ceramides; Ceramide 1-phosphate; NADPH oxidase; ROS; Proliferation; Sphingolipids
资金
- Ministerio de Ciencia e Innovacian (MICINN) (Madrid, Spain) [BFU2009-13314/BFI]
- Departamento de Educacion, Universidades e Investigacion del Gobierno Vasco (GV/EJ) [IT-353-10]
- Departamento de Industria, Comercio y Turismo del Gobierno Vasco (Basque Government, GV/EJ) [SA-2010/00013]
- National Institutes of Health [HL083187]
- Basque Government
We previously demonstrated that ceramide 1-phosphate (C1P) is mitogenic for fibroblasts and macrophages. However, the mechanisms involved in this action were only partially described. Here, we demonstrate that C1P stimulates reactive oxygen species (ROS) formation in primary bone marrow-derived macrophages, and that ROS are required for the mitogenic effect of C1P. ROS production was dependent upon prior activation of NADPH oxidase by C1P, which was determined by measuring phosphorylation of the p4Ophox subunit and translocation of p47phox from the cytosol to the plasma membrane. In addition, C1P activated cytosolic calcium-dependent phospholipase A(2) and protein kinase C-alpha, and NADPH oxidase activation was blocked by selective inhibitors of these enzymes. These inhibitors, and inhibitors of ROS production, blocked the mitogenic effect of C1P. By using BHNB-C1P (a photolabile caged-C1P analog), we demonstrate that all of these C1P actions are caused by intracellular C1P. It can be concluded that the enzyme responsible for C1P-stimulated ROS generation in bone marrow-derived macrophages is NADPH oxidase, and that this enzyme is downstream of PKC-alpha and cPLA(2)-alpha in this pathway. (C) 2011 Elsevier Inc. All rights reserved.
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