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J. Biol. Chem., Vol. 278, Issue 37, 34834-34844, September 12, 2003

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Regulation of Cyclooxygenase-2 Expression in Monocytes by Ligation of the Receptor for Advanced Glycation End Products^*

Narkunaraja Shanmugam, Young Sook Kim, Linda Lanting and Rama Natarajan 

From the Gonda Diabetes Research Center, Beckman Research Institute of the City of Hope, Duarte, California 91010

Cyclooxygenase-2 (COX-2) enzyme and its inflammatory products such as prostaglandin E₂ (PGE₂) have been implicated in the pathogenesis of several inflammatory diseases. However their role in diabetic vascular disease is unclear. Advanced glycation end products (AGEs) act via their receptor, RAGE, to play a major role in diabetic complications. In this study, we investigated the effect of AGEs and S100b, a specific RAGE ligand, on the expression of COX-2 and the molecular mechanisms involved in cultured THP-1 monocytes and human peripheral blood monocytes. S100b treatment of THP-1 cells led to a significant 3–5-fold induction of COX-2 mRNA (p < 0.001). COX-2 protein and its product PGE₂ were also increased, whereas COX-1 expression was unaffected. In vitro prepared AGE also induced COX-2 mRNA. S100b-induced COX-2 mRNA was blocked by an anti-RAGE antibody and by inhibitors of NF-B (Bay11-7082), oxidant stress, protein kinase C, ERK, and p38 MAPKs. S100b (4-h treatment) significantly increased transcription from a human COX-2 promoter-luciferase construct (4-fold, p < 0.001). Promoter deletion analyses and inhibition of transcription by an NF-B superrepressor mutant confirmed NF-B involvement. This was further supported by inhibition of S100b-induced PGE₂ by Bay11-7082. Additionally, S100b-induced adherence of THP-1 monocytes to vascular smooth muscle cells was blocked by the COX-2 inhibitor NS-398, Bay11-7082, inhibitors of ERK and p38 MAPK, and protein kinase C thereby indicating functional relevance. S100b also increased COX-2 mRNA expression in human peripheral blood monocytes from healthy donors. Moreover, COX-2 mRNA levels were clearly evident in monocytes obtained from diabetic patients but not from normal subjects. These results show for the first time that AGEs can augment inflammatory responses by up-regulating COX-2 via RAGE and multiple signaling pathways, thereby leading to monocyte activation and vascular cell dysfunction.

Received for publication, March 19, 2003 , and in revised form, June 3, 2003.

^* This work was supported by grants from the Juvenile Diabetes Research Foundation International and National Institutes of Health Grants R01DK65073 and P01HL55798. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Diabetes, Beckman Research Inst. of the City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010. Tel.: 626-359-8111 (ext. 62289); Fax: 626-301-8136; E-mail: rnatarajan{at}coh.org.

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