Pro-Inflammatory Cytokine Synthesis by Human Monocytes Induced by Proteins Minimally-Modified by Methylglyoxal

Methylglyoxal is a reactive α-oxoaldehyde, physiological metabolite and potent glycating agent. It reacts with lysine and arginine residues irreversibly to form advanced glycation endproducts (AGE): N δ -(1-carboxyethyl)lysine, 4-methylimidazolium crosslinks, hydroimidazolone, N δ -(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine and imidazolone N δ -(5-methyl-4-imidazolon-2-yl)ornithine residues. The induction of pro-inflammatory cytokines by AGE-modified protons has been suggested as a mechanism by which AGE accumulation in vivo may contribute to the development of diabetic complications and other disease mechanisms. Proteins typically have only minimal modification by AGE (1-3 AGE per protein molecule) in vivo , even in pathological states. We therefore studied the induction of cytokines in human monocytes in vitro by minimally advanced glycated proteins. Human serum albumin minimally modified by methylglyoxal stimulated the synthesis and secretion of interleukin-1β tumour necrosis factor-α and macrophage-colony stimulating factor. Human serum albumin minimally- or highly-modified by glucose-derived AGE gave a much weaker response under the same conditions. This suggests that the modification of proteins by methylglyoxal produced a potent pharmacophore for activation of the cytokine response. Cytokine induction in vivo provides a mechanism by which the accumulation of AGE, particularly methylglyoxal-modified proteins, may contribute to the development of diabetic complications, chronic renal insufficiency, Alzheimer's disease and aging.