title: A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor-alpha and induces interleukin-10 production in activated macrophages.
abstract: Tight regulation of the production of the key pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is essential for the prevention of chronic inflammatory diseases. In vivo administration of a synthetic phospholipid, named hereafter phospho-ceramide analogue-1 (PCERA-1), was previously found to suppress lipopolysaccharide (LPS)-induced TNF-alpha blood levels. We therefore investigated the in vitro anti-inflammatory effects of PCERA-1. Here, we show that extracellular PCERA-1 potently suppresses production of the pro-inflammatory cytokine TNF-alpha in RAW264.7 macrophages, and in addition, independently and reciprocally regulates the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Specificity is demonstrated by the inability of the phospholipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) to perform these activities. Similar TNF-alpha suppression and IL-10 induction by PCERA-1 were observed in macrophages when activated by Toll-like receptor 4 (TLR4), TLR2 and TLR7 agonists. Regulation of cytokine production is demonstrated at the mRNA and protein levels. Finally, we show that, while PCERA-1 does not block activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinases by LPS, it elevates the intracellular cAMP level. In conclusion, the anti-inflammatory activity of PCERA-1 seems to be mediated by a cell membrane receptor, upstream of cAMP production, and eventually TNF-alpha suppression and IL-10 induction. Thus, identification of the PCERA-1 receptor may provide new pharmacological means to block inflammation.
authors.affiliation: Department of Molecular and Structural Biochemistry, Life Sciences Institute, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Goldsmith
authors.forename: Dorit
authors.initials: D
authors.lastname: Avni
authors.forename: Galit
authors.initials: G
authors.lastname: Levy-Rimler
authors.forename: Roi
authors.initials: R
authors.lastname: Mashiach
authors.forename: Orna
authors.initials: O
authors.lastname: Ernst
authors.forename: Maya
authors.initials: M
authors.lastname: Levi
authors.forename: Bill
authors.initials: B
authors.lastname: Webb
authors.forename: Michael M
authors.initials: MM
authors.lastname: Meijler
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Tsaffrir
authors.initials: T
authors.lastname: Zor
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology; D002478:Cells, Cultured; D002518:Ceramides / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D002518:Ceramides; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C541330:PCERA-1; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
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