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J. Biol. Chem., Vol. 277, Issue 34, 30784-30791, August 23, 2002

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Ceramide Mediates Age-associated Increase in Macrophage Cyclooxygenase-2 Expression^*

Kate J. Claycombe^§, Dayong Wu^§, Mariana Nikolova-Karakashian^¶, Helen Palmer, Alison Beharka, K. Eric Paulson, and Simin Nikbin Meydani^**

From the  Nutritional Immunology Laboratory, Jean Mayer United States Department of Agriculture/Human Nutrition Research Center at Tufts University, Boston, Massachusetts 02111, the ^¶ Department of Physiology, University of Kentucky Medical School, Lexington, Kentucky 40236-0084, and the  Department of Biochemistry, Tufts University School of Medicine, Boston, Massachusetts 02111

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.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.AF344876.

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