Towards Understanding the Pathophysiological Significance of Cytokine Trapping Mediated by Advanced Glycation End Products

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  • 終末糖化産物によるサイトカイン捕捉機構の同定と病態生理学的意義の解明
  • Review for award 終末糖化産物によるサイトカイン捕捉機構の同定と病態生理学的意義の解明
  • Review for award シュウマツ トウカ サンブツ ニ ヨル サイトカイン ホソク キコウ ノ ドウテイ ト ビョウタイ セイリガクテキ イギ ノ カイメイ

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Abstract

<p>Advanced glycation end products (AGEs) are non-enzymatically formed from sugars or their metabolites with biomolecules. These molecules are formed in vivo, and the formation of AGEs on functional biomolecules was demonstrated to alter their properties. In addition, AGEs were reported to elicit inflammatory reactions by stimulating their endogenous receptors. However, the relationship between AGEs and these phenomena remains unclear. To understand the pathophysiological roles of AGEs, we investigated their action mechanisms at the molecular level. In this study, we found that AGEs can directly interact with tumor necrosis factor-like weak inducer of apoptosis (TWEAK), the cytokine that controls tumor necrosis factor-α (TNF-α)-stimulated inflammatory reactions. This interaction inhibited the action of TWEAK and subsequently increased TNF-α-induced proinflammatory cytokine expression. This raised the possibility that AGEs trap other cytokines and alter their activities. We named this hypothesis “AGE-mediated cytokine trapping”. To assess this hypothesis, we next examined the mechanism of AGE-TWEAK interaction. The pull-down assay using the deletion mutant revealed that a relatively large region of TWEAK functions in the interaction with AGEs, suggesting that it is difficult to explore other cytokines capable of interacting with AGEs using TWEAK sequence similarity. Therefore, to find novel AGE-cytokine interactions, we performed comprehensive screening using a protein array and found several candidates. To generalize “AGE-mediated cytokine trapping”, detailed studies using these candidates are now in progress.</p>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 140 (11), 1335-1341, 2020-11-01

    The Pharmaceutical Society of Japan

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