title: Ceramide 1-phosphate induces macrophage chemoattractant protein-1 release: involvement in ceramide 1-phosphate-stimulated cell migration.
abstract: 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 Gi 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-κB 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Science and Technology, University of the Basque Country (UPV/EHU), Bilbao, Spain.
authors.forename: Lide
authors.initials: L
authors.lastname: Arana
authors.forename: Marta
authors.initials: M
authors.lastname: Ordoñez
authors.forename: Alberto
authors.initials: A
authors.lastname: Ouro
authors.forename: Io-Guané
authors.initials: IG
authors.lastname: Rivera
authors.forename: Patricia
authors.initials: P
authors.lastname: Gangoiti
authors.forename: Miguel
authors.initials: M
authors.lastname: Trueba
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez-Muñoz
mesh_terms: D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002518:Ceramides / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000378:metabolism*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D002518:Ceramides; D018932:Chemokine CCL2; C065576:ceramide 1-phosphate; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases
keywords: ceramide 1-phosphate; macrophage migration; monocyte chemoattractant protein-1 release; sphingosine 1-phosphate