Advanced glycation endproducts induce self- and cross-tolerance in monocytes

Inflamm Res. 2017 Nov;66(11):961-968. doi: 10.1007/s00011-017-1076-9. Epub 2017 Jun 28.


Introduction: Advanced glycation endproducts (AGEs) are well-known inflammatory mediators, which are recognized by immune cells through their corresponding receptor RAGE and have been shown to participate in the pathophysiology of a variety of acute as well as chronic inflammatory diseases. Nevertheless, no data are available on the aftermath of AGE recognition on immune cells.

Materials and methods: We used the monocytic cell line MonoMac6 as well as primary human monocytes for double stimulation experiments. We measured secreted as well as intracellular levels of TNF-α using ELISA and flow cytometry. In addition, gene expression of surface receptors (RAGE and TLR4) and TNF were measured by qPCR.

Results: Stimulation with AGE leads to a dose-dependent induction of self- and cross-tolerance in both primary monocytes as well as the MonoMac6 cell line. The AGE tolerance depended neither on a decreased expression of RAGE or TLR4, nor on a decrease of TNF-α expression. Nevertheless, intracellular TNF-α was decreased, hinting towards a posttranscriptional regulation.

Conclusion: High levels of AGEs are capable to activate immune cells at first, but induce a secondary state of hypo-responsiveness in these cells. Based on the origin of its causal agent, we propose this phenomenon to be "metabolic tolerance".

Keywords: AGE; Inflammation; Methylglyoxal; SIRS; Sepsis.

MeSH terms

  • Cell Cycle / drug effects
  • Cell Line
  • Cells, Cultured
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • Immune Tolerance / drug effects*
  • Lipopolysaccharides / pharmacology
  • Monocytes / drug effects*
  • Monocytes / metabolism
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / metabolism


  • Glycation End Products, Advanced
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha