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Exogenous ceramide-1-phosphate (C1P) and phospho-ceramide analogue-1 (PCERA-1)
regulate key macrophage activities via distinct receptors
#MMPMID26656944
Katz S
; Ernst O
; Avni D
; Athamna M
; Philosoph A
; Arana L
; Ouro A
; Hoeferlin LA
; Meijler MM
; Chalfant CE
; Gómez-Muñoz A
; Zor T
Immunol Lett
2016[Jan]; 169
(?): 73-81
PMID26656944
show ga
Inflammation is an ensemble of tightly regulated steps, in which macrophages play
an essential role. Previous reports showed that the natural sphingolipid ceramide
1-phosphate (C1P) stimulates macrophages migration, while the synthetic C1P
mimic, phospho-ceramide analogue-1 (PCERA-1), suppresses production of the key
pro-inflammatory cytokine TNF? and amplifies production of the key
anti-inflammatory cytokine IL-10 in LPS-stimulated macrophages, via one or more
unidentified G-protein coupled receptors. We show that C1P stimulated RAW264.7
macrophages migration via the NF?B pathway and MCP-1 induction, while PCERA-1
neither mimicked nor antagonized these activities. Conversely, PCERA-1
synergistically elevated LPS-dependent IL-10 expression in RAW264.7 macrophages
via the cAMP-PKA-CREB signaling pathway, while C1P neither mimicked nor
antagonized these activities. Interestingly, both compounds have the capacity to
additively inhibit TNF? secretion; PCERA-1, but not C1P, suppressed LPS-induced
TNF? expression in macrophages in a CREB-dependent manner, while C1P, but not
PCERA-1, directly inhibited recombinant TNF? converting enzyme (TACE). Finally,
PCERA-1 failed to interfere with binding of C1P to either the cell surface
receptor or to TACE. These results thus indicate that the natural sphingolipid
C1P and its synthetic analog PCERA-1 bind and activate distinct receptors
expressed in RAW264.7 macrophages. Identification of these receptors will be
instrumental for elucidation of novel activities of extra-cellular sphingolipids,
and may pave the way for the design of new sphingolipid mimics for the treatment
of inflammatory diseases, and pathologies which depend on cell migration, as in
metastatic tumors.
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