期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 304, 期 11, 页码 E1213-E1226出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00480.2012
关键词
ceramide 1-phosphate; monocyte chemoattractant protein-1 release; macrophage migration; sphingosine 1-phosphate
资金
- Ministerio de Ciencia e Innovacion (MICINN) (Madrid, Spain) [BFU2009-13314/BFI]
- Departamento de Educacion, Universidades e Investigacion del Gobierno Vasco (GV/EJ, Spain) [IT-705-13]
- Departamento de Industria, Comercio y Turismo del Gobierno Vasco (Basque Government, GV/EJ, Spain) [S-PE11UN017, S-PE12UN040]
- Basque Government
- MICINN
- University of the Basque Country (GV/EJ, Spain)
The bioactive sphingolipid ceramide 1-phosphate (C1P) is implicated in inflammatory responses and was recently shown to promote cell migration. However, the mechanisms involved in these actions are poorly described. Using J774A. 1 macrophages, we have now discovered a new biological activity of C1P: stimulation of monocyte chemoattractant protein-1 (MCP-1) release. This novel effect of C1P was pertussis toxin (PTX) sensitive, suggesting the intervention of G(i) protein-coupled receptors. Treatment of the macrophages with C1P caused activation of the phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase kinase (MEK)/extracellularly regulated kinases (ERK), and p38 pathways. Inhibition of these kinases using selective inhibitors or specific siRNA blocked the stimulation of MCP-1 release by C1P. C1P stimulated nuclear factor-kappa B activity, and blockade of this transcription factor also resulted in complete inhibition of MCP-1 release. Also, C1P stimulated MCP-1 release and cell migration in human THP-1 monocytes and 3T3-L1 preadipocytes. A key observation was that sequestration of MCP-1 with a neutralizing antibody or treatment with MCP-1 siRNA abolished C1P-stimulated cell migration. Also, inhibition of the pathways involved in C1P-stimulated MCP-1 release completely blocked the stimulation of cell migration by C1P. It can be concluded that C1P promotes MCP-1 release in different cell types and that this chemokine is a major mediator of C1P-stimulated cell migration. The PI3K/Akt, MEK/ERK, and p38 pathways are important downstream effectors in this action.
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