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Anti-Inflammatory Effects of the Advanced Glycation End Product Inhibitor LR-90 in Human Monocytes

From the Department of Diabetes, Endocrinology and Metabolism, Beckman Research Institute of the City of Hope National Medical Center, Duarte, California

Address correspondence and reprint requests to Prof. Samuel Rahbar, MD, PhD, Department of Diabetes, Endocrinology and Metabolism, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA 91010. E-mail: srahbar{at}coh.org

Abbreviations: AGE, advanced glycation end product; COX-2, cycloxygenase-2; DHE, dihydroethidine; DPI, diphenyleneiodonium; ELISA, enzyme-linked immunosorbent assay; HUVEC, human umbilical vein endothelial cell; IP-10, interferon-–inducible protein-10; MCP-1, monocyte chemoattractant protein-1; NF-B, nuclear factor-B; NOX2, NADPH oxidase; RAGE, receptor for AGE; ROS, reactive oxygen species; TNF-, tumor necrosis factor-

Ligation of advanced glycation end products (AGEs) with their receptor (RAGE) plays an important role in the development of various diabetes complications, including atherosclerosis. Monocyte activation, adhesion, and migration are key events in the pathogenesis of atherosclerosis. Previous studies showed that AGEs and S100b, a specific RAGE ligand, could augment monocyte inflammatory responses via RAGE. In this study, we examined whether LR-90, a compound belonging to a new class of AGE inhibitor, could inhibit inflammatory responses in human monocytes. Human THP-1 cells were pretreated with LR-90 and then stimulated with S100b. LR-90 significantly inhibited S100b-induced expression of RAGE and other proinflammatory genes including monocyte chemoattractant protein-1, interferon-–inducible protein-10, and cyclooxygenase-2 in a dose-dependent manner. These inhibitory effects may be exerted via inhibition of nuclear factor-B (NF-B) activation, as LR-90 suppressed both S100b–and tumor necrosis factor-–induced IB- degradation as well as NF-B promoter transcriptional activity. LR-90 also prevented oxidative stress in activated monocytes, as demonstrated by its inhibitory effects on S100b-induced expression of NADPH oxidase and intracellular superoxide production. In addition, LR-90 blocked S100b-induced monocyte adhesion to human umbilical vein endothelial cell. These new data show that, in addition to its AGE inhibitory effects, LR-90 has novel anti-inflammatory properties and might therefore have additional protective effects against diabetic vascular complications.

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