Advanced glycation end products (AGEs) synergistically potentiated the proinflammatory action of lipopolysaccharide (LPS) and high mobility group box-1 (HMGB1) through their direct interactions

Masahiro Watanabe, Takao Toyomura, Mayuko Tomiyama, Hidenori Wake, Keyue Liu, Kiyoshi Teshigawara, Hideo Takahashi, Masahiro Nishibori, Shuji Mori

Research output: Contribution to journalArticlepeer-review

Abstract

Previously, we found that advanced glycation endproducts (AGEs) directly interact with tumor necrosis factor (TNF)-like weak inducer of apoptosis, a cytokine that controls inflammation, and that this interaction inhibited its action. This finding raised the novel possibility that AGEs alter the function of other cytokines through direct interaction. To investigate this possibility, we performed comprehensive screening for candidates that interacted with AGEs using protein array analysis. The array analysis revealed that high mobility group box-1 (HMGB1) had a markedly high affinity for AGEs. HMGB1 is a representative proinflammatory damage-associated molecular pattern molecule, and is reported to interact with lipopolysaccharide (LPS) directly to exert its inflammatory function. When LPS, HMGB1, and AGEs were mixed, the mobility of HMGB1 had shifted significantly in native PAGE, suggesting that these three molecules formed a triplet complex. The addition of AGEs to the LPS–HMGB1 mixture synergistically potentiated LPS–HMGB1-stimulated TNF-α mRNA expression in macrophage-like RAW264.7 cells. In addition, using receptor knockout clones, the increased proinflammatory response by LPS–HMGB1–AGEs complex was demonstrated to be mediated via Toll-like receptor 4 and receptor for AGEs. Taken together, this study suggested that AGEs carry out their pathophysiological roles by potentiating the LPS–HMGB1-stimulated proinflammatory response through direct interactions.

Original languageEnglish
Pages (from-to)7153-7159
Number of pages7
JournalMolecular Biology Reports
Volume47
Issue number9
DOIs
Publication statusPublished - Sep 1 2020

Keywords

  • Advanced glycation end products
  • High mobility group box-1
  • Lipopolysaccharide
  • Receptor for advanced glycation end products
  • Toll-like receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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