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Diabetes 53:795-802, 2004
© 2004 by the American Diabetes Association, Inc.

Molecular Mechanisms of High Glucose-Induced Cyclooxygenase-2 Expression in Monocytes

Narkunaraja Shanmugam, Irene T. Gaw Gonzalo, and Rama Natarajan

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

The cyclooxygenase (COX)-2 enzyme has been implicated in the pathogenesis of several inflammatory diseases. However, its role in diabetic vascular disease is unclear. In this study, we evaluated the hypothesis that diabetic conditions can induce COX-2 in monocytes. High glucose treatment of THP-1 monocytic cells led to a significant three- to fivefold induction of COX-2 mRNA and protein expression but not COX-1 mRNA. High glucose-induced COX-2 mRNA was blocked by inhibitors of nuclear factor-{kappa}B (NF-{kappa}B), protein kinase C, and p38 mitogen-activated protein kinase. In addition, an antioxidant and inhibitors of mitochondrial superoxide, NADPH oxidase, and glucose metabolism to glucosamine also blocked high glucose-induced COX-2 expression to varying degrees. High glucose significantly increased transcription from a human COX-2 promoter-luciferase construct (twofold, P < 0.001). Promoter deletion analyses and inhibition of transcription by NF-{kappa}B superrepressor and cAMP-responsive element binding (CREB) mutants confirmed the involvement of NF-{kappa}B and CREB transcription factors in high glucose-induced COX-2 regulation. In addition, isolated peripheral blood monocytes from type 1 and type 2 diabetic patients had high levels of COX-2 mRNA, whereas those from normal volunteers showed no expression. These results show that high glucose and diabetes can augment inflammatory responses by upregulating COX-2 via multiple signaling pathways, leading to monocyte activation relevant to the pathogenesis of diabetes complications.

Address correspondence and reprint requests to Rama Natarajan, PhD, Department of Diabetes, Beckman Research Institute of City of Hope, 1500 East Duarte Rd., Duarte, CA 91010. E-mail: rnatarajan{at}coh.org


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