Ceramide mediates age-associated increase in macrophage cyclooxygenase-2 expression.
Previously, we showed that macrophages (MØ) from old mice have significantly higher levels of lipopolysaccharide (LPS)-induced prostaglandin E(2) (PGE(2)) production than young mice, due to increased cyclooxygenase-2 (COX-2) mRNA levels. The aim of the current study was to determine the underlying mechanisms of age-associated increase in COX-2 gene expression. The results demonstrate that increased COX-2 mRNA expression in the old mice is due to a higher rate of transcription rather than increased stability of COX-2 mRNA. Furthermore, the results show that LPS-induced ceramide levels from the old mice are significantly higher than those of young mice, whereas there is no age-related difference in concentration of its down stream metabolite, sphingosine. The addition of ceramide in the presence or absence of LPS resulted in a significant increase in PGE(2) production in a dose- and time-dependent manner. Inhibition of ceramide conversion to sphingosine had no effect on this ceramide-induced effect. The ceramide-induced up-regulation in PGE(2) production was mediated through increase in COX activity and transcriptional up-regulation of COX-2 mRNA. Collectively, these data suggest that the age-associated increase in MØ COX-2 mRNA is due to transcriptional up-regulation. Furthermore, this increase in transcription is mediated by higher cellular ceramide concentration in old MØ compared with that of young MØ.
Claycombe
Kate J
KJ
Nutritional Immunology Laboratory, Jean Mayer United States Department of Agriculture/Human Nutrition Research Center at Tufts University, 711 Washington Street, Boston, MA 02111.
Wu
Dayong
D
Nikolova-Karakashian
Mariana
M
Palmer
Helen
H
Beharka
Alison
A
Paulson
K Eric
KE
Meydani
Simin Nikbin
SN
D000367:Age Factors; D000818:Animals; D001483:Base Sequence; D002518:Ceramides / Q000502:physiology*; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000096:biosynthesis; D007527:Isoenzymes / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D013110:Sphingosine / Q000502:physiology; D014158:Transcription, Genetic
D002518:Ceramides; D007527:Isoenzymes; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone; D013110:Sphingosine