Molecular and Cellular Biochemistry

, Volume 434, Issue 1–2, pp 153–162 | Cite as

Advanced glycation end products attenuate the function of tumor necrosis factor-like weak inducer of apoptosis to regulate the inflammatory response

  • Masahiro Watanabe
  • Takao Toyomura
  • Hidenori Wake
  • Keyue Liu
  • Kiyoshi Teshigawara
  • Hideo Takahashi
  • Masahiro Nishibori
  • Shuji MoriEmail author


Advanced glycation end products (AGEs) are formed from the non-enzymatic glycation reaction of reducing sugars or their metabolites with the free amino groups of several biomolecules and are known to play pathophysiological roles in various inflammatory diseases. In an earlier study, it was suggested that tumor necrosis factor-like weak inducer of apoptosis (TWEAK) has a unique role to regulate the tumor necrosis factor α (TNFα)-induced inflammatory response. In this study, we investigated the effect of the AGEs–TWEAK interaction on proinflammatory signaling responses in endothelial cells and the influence of AGEs on the cellular function of TWEAK in the inflammatory process. The effect of AGEs on the TWEAK/TNFα-induced gene expression of interleukin-8 (IL-8) was determined by real-time RT-PCR in endothelial-like EA.hy.926 cells. The pull-down assay was performed using recombinant His-tagged TWEAK and AGEs. The NF-κB activation was analyzed by Western blotting with canonical and non-canonical pathway-specific antibodies. AGEs dose-dependently inhibited TWEAK-induced IL-8 gene expression, whereas AGEs themselves had almost no effect on IL-8 expression. AGEs were found to bind directly to TWEAK in the pull-down assay. TNFα-induced IL-8 production and canonical NF-κB activation were suppressed by TWEAK pretreatment, whereas TWEAK-induced non-canonical NF-κB activation was enhanced by pretreatment. These effects induced by TWEAK pretreatment were abolished by the co-addition of AGEs. Our findings suggest that AGEs attenuate the function of TWEAK to regulate the TNFα-induced inflammatory responses, which provide important clues for understanding the significance of the AGEs–TWEAK interaction in inflammatory processes.


Advanced glycation end products Inflammatory response Cytokine Tumor necrosis factor 



This work was supported by the Japan Society for the Promotion of Science [Grant Nos. 15K08605 and 15H06785] and the Mitsui Sumitomo Insurance Welfare Foundation.


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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Masahiro Watanabe
    • 1
  • Takao Toyomura
    • 1
  • Hidenori Wake
    • 2
  • Keyue Liu
    • 2
  • Kiyoshi Teshigawara
    • 2
  • Hideo Takahashi
    • 3
  • Masahiro Nishibori
    • 2
  • Shuji Mori
    • 1
    Email author
  1. 1.Department of Pharmacology, School of PharmacyShujitsu UniversityOkayamaJapan
  2. 2.Department of PharmacologyOkayama University Graduate School of Medicine, Dentistry, and Pharmaceutical SciencesOkayamaJapan
  3. 3.Department of Pharmacology, Faculty of MedicineKindai UniversityOsakaJapan

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