TY - JOUR
T1 - Ceramide mediates age-associated increase in macrophage cyclooxygenase-2 expression
AU - Claycombe, Kate J.
AU - Wu, Dayong
AU - Nikolova-Karakashian, Mariana
AU - Palmer, Helen
AU - Beharka, Alison
AU - Eric Paulson, K.
AU - Meydani, Simin Nikbin
PY - 2002/8/23
Y1 - 2002/8/23
N2 - Previously, we showed that macrophages (MØ) from old mice have significantly higher levels of lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) 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 PGE2 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 PGE2 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.
AB - Previously, we showed that macrophages (MØ) from old mice have significantly higher levels of lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) 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 PGE2 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 PGE2 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.
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U2 - 10.1074/jbc.M204463200
DO - 10.1074/jbc.M204463200
M3 - Article
C2 - 12072440
AN - SCOPUS:0037163119
SN - 0021-9258
VL - 277
SP - 30784
EP - 30791
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -