Naturally occurring flavonoids attenuate high glucose-induced expression of proinflammatory cytokines in human monocytic THP-1 cells

Activation of circulating monocytes by hyperglycemia is bound to play a role in inflammatory and atherosclerosis. In this study, we examined whether flavonoids (catechin, EGCG, luteolin, quercetin, rutin) - phytochemicals that may possible belong to a new class of advanced glycation end products (AGEs) inhibitors - can attenuate high glucose (15 mmol/L, HG)-induced inflammation in human monocytes. Our results show that all flavonoids significantly inhibited HG-induced expression of proinflammatory genes and proteins, including TNF-α, interleukin-1β (IL-1β), and cyclooxygenase (COX)-2, at a concentration of 20 μM. Flavonoids also prevented oxidative stress in activated monocytes, as demonstrated by their inhibitory effects on intracellular reactive oxygen species (ROS) and N^ε-(carboxymethyl)lysine formation caused by HG. These inhibitory effects may involve inhibition of nuclear factor-κB activation and may be supported by downregulation of the following: i) PKCdependent NADPH oxidase pathway; ii) phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated protein kinase, and iii) mRNA expression of receptor of AGEs. In addition, we found for the first time that lower levels of Bcl-2 protein under HG conditions could be countered by the action of flavonoids. Our data suggest that, along with their antioxidant activities, flavonoids possess anti-inflammatory properties and might therefore have additional protective effects against glycotoxin-related inflammation.