Transcriptional repression of ceramide kinase in LPS-challenged macrophages

Ceramide kinase (CERK) produces the bioactive lipid ceramide 1-phosphate (C1P). Both CERK and C1P have been identified as mediators of cell growth and survival. Recent evidence showed that CERK is down-regulated during M1-type macrophage activation, which is known to promote cell growth arrest. However, the mechanism has not been investigated yet and, in particular, whether growth arrest might be the signal for down-regulation of CERK is currently unknown. Here, we found that LPS-mediated TLR-4 engagement reduces Cerk mRNA levels in mouse primary macrophages. Reporter gene assays in RAW264.7 macrophages showed that LPS inhibits the transcriptional activity of the Cerk proximal promoter. The G1-cell cycle blocker mimosine did not inhibit Cerk transcription, suggesting that transcriptional repression of Cerk by LPS is not a primary consequence of LPS-induced cell cycle blockade.

Research highlights
► Transcription of ceramide kinase is down-regulated in LPS-challenged primary macrophages, in contrast to glucosylceramide synthase and sphingomyelin synthase.
► Inhibition of ceramide kinase transcription occurs through negative regulation of its proximal promoter.
► Inhibition of the ceramide kinase promoter by LPS is not a consequence of cell cycle blockade.