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Proinflammatory Effects of Advanced Lipoxidation End Products in Monocytes

¹ Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, California
² DNA, RNA, and Peptide Synthesis Laboratory, Beckman Research Institute of City of Hope, Duarte, California

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

Abbreviations: AGE, advanced glycation end product; ALE, advanced lipoxidation end product; CCL, chemokine CC motif ligand; CML, carboxymethyl-lysine; COX-2, cyclooxygenase-2; DCF, 2'-7'-dichlorofluorescein; DHE, dihydroethidine; EMSA, electrophoretic mobility shift assay; ERK, extracellular signal–regulated kinase; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFX, bis-indolylmaleimide; HNE, 4-hydroxy-nonenal; HUVEC, human umbilical vein endothelial cell; HVSMC, human vascular smooth muscle cell; IL, interleukin; iNOS, inducible nitric-oxide synthase; MAPK, mitogen-activated protein kinase; MCP-1, monocyte chemoattractant protein-1; MDA-Lys, malondialdehyde-lysine; NAC, N-acetylcysteine; NF-B, nuclear factor-B; PKC, protein kinase C; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; STZ, streptozotocin; VSMC, vascular smooth muscle cell

OBJECTIVE—The reactions of carbohydrate- or lipid-derived intermediates with proteins lead to the formation of Maillard reaction products, which subsequently leads 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 proinflammatory effects in monocytes.

RESEARCH DESIGN AND METHODS—In a profiling approach, conditioned media from THP-1 cells either cultured in normal glucose (5.5 mmol/l) or treated with MDA-Lys or MDA alone were hybridized to arrays containing antibodies to 120 known human cytokines/chemokines. Pathway analyses with bioinformatics software were used to identify signalling networks.

RESULTS—Synthetic ALE (malondialdehyde-lysine [MDA-Lys]) (50 µmol/l) could induce oxidant stress and also activate the transcriptional factor nuclear factor-B (NF-B) in THP-1 monocytes. MDA-Lys also significantly increased the expression of key candidate proinflammatory genes, interferon-–inducible protein-10, β1- and β2-integrins, cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 and -8, and inducible nitric-oxide synthase, which are also associated with monocyte dysfunction. Several key target proinflammatory proteins were significantly induced by MDA-Lys relative to normal glucose or MDA alone, including MCP-1; tumor necrosis factor ligand superfamily member-14; chemokine CC motif ligand-11 (CCL11); growth-related oncogene-, -β, and -; and chemokine CXC motif ligand-13. Bioinformatics analyses identified a network of chemokine signaling among 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 and CCL11.

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

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