title: Sphingosylphosphorylcholine and lysosulfatide have inverse regulatory functions in monocytic cell differentiation into macrophages.
abstract: Sphingolipids act as signaling mediators that regulate a diverse range of cellular events. Although numerous sphingolipid functions have been studied, little is known about the effect of sphingolipids on monocyte differentiation into macrophages. Here, we report that two lysosphingolipids, sphingosylphosphorylcholine (SPC) and lysosulfatide (LSF), inversely affect macrophagic differentiation of monocytic cell lines, U937 and THP-1. Molecular analyses revealed that SPC enhances, whereas LSF suppresses, phorbol ester-induced classical (M1-polarized) differentiation to macrophages. The expression of CD11b, a macrophage marker, was induced in accordance with the activation status of the Raf/MEK/ERK signaling pathway in which SPC and LSF had opposite effects. Pharmacological inhibition of this pathway aborted the differentiation, indicating that this signaling pathway is required. Consistently, SPC promoted, while LSF inhibited, monocyte adhesion to fibronectin, through the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. The effects of SPC on Raf/MEK/ERK and PI3K/Akt signaling were dependent on G(i/o), whereas the SPC-induced calcium influx was dependent on G(q). Thus SPC utilizes G-protein coupled receptor. In contrast, the effects of LSF were independent of G(i/o) and G(q). These results suggest that SPC enhances, whereas LSF suppresses, monocyte differentiation into macrophages through regulating the Raf/MEK/ERK and PI3K/Akt signaling pathways via distinct mechanisms.
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Sakyo, Kyoto 606-8501, Japan; CREST, JST, Kawaguchi, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Naito
authors.forename: Maho
authors.initials: M
authors.lastname: Okano
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kanazawa
authors.forename: Hiromu
authors.initials: H
authors.lastname: Takematsu
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Kozutsumi
mesh_terms: D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011609:Psychosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D020298:U937 Cells; D048490:raf Kinases / Q000378:metabolism
chemical_list: D017931:DNA Primers; D049349:Receptors, Lysosphingolipid; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D011609:Psychosine; C019064:psychosine-3'-sulfate ester; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium