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Pro-inflammatory Effects of Advanced Lipoxidation End Products in Monocytes.

¹ Department of Diabetes
^¶DNA RNA & Peptide Synthesis Lab, Beckman Research Institute of City of Hope, 1500 East Duarte Road, Duarte, CA 91010

Background: The reactions of carbohydrate or lipid derived intermediates with proteins lead to the formation of Maillard reaction products, which subsequently lead to the formation of advanced glycation/lipoxidation end products (AGE/ALEs). Levels of AGE/ALEs are increased in diseases like diabetes. Unlike AGEs, very little is known about ALE effects in vitro. We hypothesized that ALEs can have pro-inflammatory effects in monocytes.

Methods and Results: Synthetic ALE (malondialdehyde-lysine, MDA-Lys) (50µmol/l) could induce oxidant stress and also activate the transcriptional factor NF-B in THP-1 monocytes. MDA-Lys also significantly increased the expression of key candidate pro-inflammatory genes, Interferon--inducible protein-10, ß1 and ß2-Integrins, cyclooxygenase-2, monocyte chemoattractant protein-1 (MCP-1), interleukins-6 and-8, and iNOS that are also associated with monocyte dysfunction. In a profiling approach, conditioned media from THP-1 cells cultured either in normal glucose (NG, 5.5 mM) or treated with MDA-Lys or MDA alone were hybridized to arrays containing antibodies to 120 known human cytokines/chemokines. Several key target pro-inflammatory proteins were significantly induced by MDA-Lys relative to NG or MDA alone, including MCP-1, TNF ligand superfamily member-14, Chemokine CC motif Ligand-11 (CCL-11), Growth Related Oncogene , ß, , and Chemokine CXC motif Ligand-13. Pathway analyses with bioinformatics software identified a network of chemokine signaling amongst MDA-Lys regulated genes. MDA-Lys also increased monocyte binding to vascular smooth muscle and endothelial cells. Furthermore, plasma from diabetic rats showed significantly higher levels of MDA-Lys as well as CCL11.

Conclusion: These new results suggest that ALEs can promote monocyte activation and vascular complications via induction of inflammatory pathways and networks.

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