Proinflammatory effects of advanced lipoxidation end products in monocytes.
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.


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 micromol/l) could induce oxidant stress and also activate the transcriptional factor nuclear factor-kappaB (NF-kappaB) in THP-1 monocytes. MDA-Lys also significantly increased the expression of key candidate proinflammatory genes, interferon-gamma-inducible protein-10, beta1- and beta2-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-alpha, -beta, and -gamma; 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.
Shanmugam
Narkunarajaa
N
Department of Diabetes, Beckman Research Institute of the City of Hope, 1500 East Duarte Rd., Duarte, CA 91010, USA.
Figarola
James L
JL
Li
Yan
Y
Swiderski
Piotr M
PM
Rahbar
Samual
S
Natarajan
Rama
R
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D015227:Lipid Peroxidation / Q000502:physiology*; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D054390:Receptors, CCR2 / Q000235:genetics
D017127:Glycation End Products, Advanced; C464486:N(epsilon)-(malondialdehyde)lysine; D016328:NF-kappa B; D054390:Receptors, CCR2; D051546:Cyclooxygenase 2; D005947:Glucose; D008239:Lysine; D000111:Acetylcysteine