A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor-α and induces interleukin-10 production in activated macrophages

Meir Goldsmith, Dorit Avni, Galit Levy-Rimler, Roi Mashiach, Orna Ernst, Maya Levi, Bill Webb, Michael M. Meijler, Nathanael S. Gray, Hugh Rosen, Tsaffrir Zor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Tight regulation of the production of the key pro-inflammatory cytokine tumour necrosis factor-α (TNF-α) 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-α 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-α 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-α 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)-κB 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-α suppression and IL-10 induction. Thus, identification of the PCERA-1 receptor may provide new pharmacological means to block inflammation.

Original languageEnglish
Pages (from-to)103-115
Number of pages13
JournalImmunology
Volume127
Issue number1
DOIs
StatePublished - May 2009

Keywords

  • Cytokines
  • Inflammation
  • Interleukin-10
  • Lipopolysaccharide
  • Tumour necrosis factor

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