Dietary Advanced Glycation Endproducts Induce an Inflammatory Response in Human Macrophages in Vitro

Abstract

Advanced glycation endproducts (AGEs) can be found in protein- and sugar-rich food products processed at high temperatures, which make up a vast amount of the Western diet. The effect of AGE-rich food products on human health is not yet clear and controversy still exists due to possible contamination of samples with endotoxin and the use of endogenous formed AGEs. AGEs occur in food products, both as protein-bound and individual molecules. Which form exactly induces a pro-inflammatory effect is also unknown. In this study, we exposed human macrophage-like cells to dietary AGEs, both in a protein matrix and individual AGEs. It was ensured that all samples did not contain endotoxin concentrations > 0.06 EU/mL. The dietary AGEs induced TNF-alpha secretion of human macrophage-like cells. This effect was decreased by the addition of N(ε)-carboxymethyllysine (CML)-antibodies or a receptor for advanced glycation endproducts (RAGE) antagonist. None of the individual AGEs induce any TNF-alpha, indicating that AGEs should be bound to proteins to exert an inflammatory reaction. These findings show that dietary AGEs directly stimulate the inflammatory response of human innate immune cells and help us define the risk of regular consumption of AGE-rich food products on human health.

Dietary advanced glycation end‐products: Perspectives linking food processing with health implications

“…Numerous studies have implied that the AGE‐RAGE axis contributes to the pathogenesis of chronic diseases, while most of them deal with endogenous AGEs (e.g., AGE‐albumin conjugates), not AGEs directly related to heat‐processed foods or Western‐style diets. In cell cultures, several food‐derived AGEs were shown to activate inflammatory responses via a RAGE‐dependent pathway (Somoza et al., 2005; Van der Lugt et al., 2018; Zill et al., 2003; Zill, Günther, Erbersdobler, Fölsch, & Faist, 2001). In rodent models, high‐dAGE diets deteriorated pathogenesis mediated by RAGE that are associated with diabetes (Borg et al., 2018; Lin et al., 2003), nephropathies (Yeh, Yang, Pai, Wu, & Chen, 2017), vascular dysfunction (Tikellis et al., 2008), nonalcoholic steatohepatitis (Leung et al., 2016), and Alzheimer's disease (Lubitz et al., 2016).…”

Dietary Advanced Glycation Endproducts Decrease Glucocorticoid Sensitivity In Vitro

“…Dietary AGEs were prepared as described previously [18]. In short, casein, glucose, and lactose, in the proportions of milk powder (11 mM glucose, 0.2 M lactose, 10 g/L casein from bovine milk), were dissolved in 50 mM phosphate buffer (pH = 7.4) and heated in an Erlenmeyer flask on a heating plate at 100 • C for up to 15 min.…”

“…After 15 min, a sample was taken out and put in ice water. Samples were aliquoted and stored at −80 • C. The concentrations of several individual AGEs have been published in our previous study [18]. MG-H1 was present in concentrations of 1.6 ± 0.9 µg/mL (mean ± standard deviation (SD)); the CML concentration was 0.6 ± 0.5 µg/mL.…”

“…Recently, a study of ours was one of the first to show that dietary advanced glycation endproducts (AGEs) cause inflammation in human macrophages in vitro by binding to the receptor for advanced glycation endproducts (RAGE) [18]. After activation, RAGE signaling leads to the activation of NF-κB via PI3K and additionally to the activation of p38MAPK.…”

Bacterial processing of glucose modulates C. elegans lifespan and healthspan

“…Additionally, dietary AGEs have been shown to affect the inflammatory response in cell culture 24 , but there are mixed results for the effects of dietary AGEs in human trials 22 . Emerging studies also suggest that dietary AGEs can contribute to the onset of organ damage, affect metabolic control, and therefore impact global health 23 .…”