Advanced glycation end products (AGEs) synergistically potentiated the proinflammatory action of lipopolysaccharide (LPS
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ORIGINAL ARTICLE
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 Watanabe1 · Takao Toyomura1 · Mayuko Tomiyama1 · Hidenori Wake2 · Keyue Liu2 · Kiyoshi Teshigawara2 · Hideo Takahashi3 · Masahiro Nishibori2 · Shuji Mori1 Received: 9 May 2020 / Revised: 10 August 2020 / Accepted: 28 August 2020 © Springer Nature B.V. 2020
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. Keywords Advanced glycation end products · High mobility group box-1 · Lipopolysaccharide · Receptor for advanced glycation end products · Toll-like receptor
Introduction Advanced glycation end products (AGEs) were initially found as the cause of food browning. These molecules are formed in vivo from reducing sugar or its metabolites with the free amino groups of endogenous molecules such as * Shuji Mori [email protected] 1
Department of Pharmacology, School of Pharmacy, Shujitsu University, 1‑6‑1 Nishigawara, Naka‑Ku, 703‑8516 Okayama, Japan
2
Department of Pharmacology, Dentistry, and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2‑5‑1 Shikata‑cho, 700‑8558 Okayama, Japan
3
Department of Pharmacology, Faculty of Medicine, Kindai University, 377‑2 Ohno‑Higashi, 589‑8511 Osaka‑Sayama, Japan
proteins and lipids. Furthermore, the accumulation of AGEs in vivo was suggested to be involved in the pathogenesis of aging-related diseases, hyperglycemia, and some inflammatory diseases such as diabetes and cardiovascular disease [1–5]. As the
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