Synergistic IL-10 induction by LPS and the ceramide-1-phosphate analog PCERA-1 is mediated by the cAMP and p38 MAP kinase pathways

Meir Goldsmith, Dorit Avni, Orna Ernst, Yifat Glucksam, Galit Levy-Rimler, Michael M. Meijler, Tsaffrir Zor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Expression of the anti-inflammatory cytokine IL-10 can be induced either by TLR agonists such as lipopolysaccharide (LPS), or by various endogenous stimuli, in particular those acting via a cAMP-dependent signaling pathway. We have previously reported that the synthetic phospho-ceramide analogue-1 (PCERA-1) increases cAMP level and subsequently down-regulates production of TNFα and up-regulates production of IL-10 in LPS-stimulated macrophages. The objective of this study was to determine the mechanism of activity of PCERA-1 and the role of cAMP in LPS-induced IL-10 production. We show here that PCERA-1 induces IL-10 production in synergism with various TLR agonists in mouse RAW264.7 macrophages. Cooperativity is evident both at the mRNA and protein levels. IL-10 production by LPS and PCERA-1 is mediated by the cAMP pathway and by the p38 MAP kinase. Phosphorylation of p38 is cooperatively accomplished by LPS and PCERA-1 or other cAMP inducers. Furthermore, the activity of PCERA-1 can be partially mimicked by a cell-permeable analog of cAMP, and blocked by the protein kinase A (PKA) inhibitor H89. Finally, in the absence of PCERA-1, the residual IL-10 induction by LPS depends on the basal cAMP level as it can be largely elevated by the phosphodiesterase (PDE)-4 inhibitor rolipram. Our results thus indicate that IL-10 induction by LPS critically depends on basal cAMP level, and that a co-stimulus by a TLR agonist and a cAMP-elevating agent results in synergistic PKA-dependent and p38-dependent IL-10 production.

Original languageEnglish
Pages (from-to)1979-1987
Number of pages9
JournalMolecular Immunology
Issue number10
StatePublished - Jun 2009


FundersFunder number
Israel's Ministry of Absorption
Israel's ministry of justice3223
Teva Pharmaceutical Industries
European Commission021862
Israel Science Foundation907/07


    • IL-10
    • Inflammation
    • Lipopolysaccharide
    • Macrophages
    • Phospholipid signaling
    • cAMP
    • p38 MAP kinase


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