Proinflammatory Effects of Advanced Lipoxidation End Products in Monocytes

  1. Rama Natarajan1
  1. 1Department of Diabetes, Beckman Research Institute of City of Hope, Duarte, California
  2. 2DNA, RNA, and Peptide Synthesis Laboratory, Beckman Research Institute of City of Hope, Duarte, California
  1. 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

Abstract

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-κB (NF-κB) in THP-1 monocytes. MDA-Lys also significantly increased the expression of key candidate proinflammatory genes, interferon-γ–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-α, -β, and -γ; 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.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 11 November 2007. DOI: 10.2337/db07-1204.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-1204.

    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.

    • Received August 24, 2007.
    • Accepted November 3, 2007.
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  1. Diabetes vol. 57 no. 4 879-888
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