2. Academic Validation
  3. Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages

Trimebutine suppresses Toll-like receptor 2/4/7/8/9 signaling pathways in macrophages

  • Arch Biochem Biophys. 2021 Oct 30:711:109029. doi: 10.1016/j.abb.2021.109029.
Natsumi Ogawa 1,  Shingo Nakajima 1,  Kenya Tamada 1,  Natsuki Yokoue 1,  Haruki Tachibana 1,  Miwa Okazawa 2,  Takahiro Oyama 3,  Hideaki Abe 3,  Hiroaki Yamazaki 3,  Atsushi Yoshimori 4,  Akira Sato 1,  Takanori Kamiya 5,  Takehiko Yokomizo 6,  Fumiaki Uchiumi 7,  Takehiko Abe 5,  Sei-Ichi Tanuma 8
Affiliations

Affiliations

  • 1 Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
  • 2 Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
  • 3 Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan.
  • 4 Institute for Theoretical Medicine, Inc., Fujisawa, Kanagawa, 251-0012, Japan.
  • 5 Hinoki Shinyaku Co., Ltd., Chiyoda-ku, Tokyo, 102-0084, Japan.
  • 6 Department of Biochemistry, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, 113-8421, Japan.
  • 7 Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan.
  • 8 Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, 278-8510, Japan; Department of Genomic Medicinal Science, Research Institute for Science and Technology, Organization for Research Advancement, Tokyo University of Science, Noda, Chiba, 278-8510, Japan. Electronic address: tanuma@rs.tus.ac.jp.
PMID: 34517011 DOI: 10.1016/j.abb.2021.109029
Abstract

Because of the critical roles of Toll-like receptors (TLRs) and receptor for advanced glycation end-products (RAGE) in the pathophysiology of various acute and chronic inflammatory diseases, continuous efforts have been made to discover novel therapeutic inhibitors of TLRs and RAGE to treat inflammatory disorders. A recent study by our group has demonstrated that trimebutine, a spasmolytic drug, suppresses the high mobility group box 1‒RAGE signaling that is associated with triggering proinflammatory signaling pathways in macrophages. Our present work showed that trimebutine suppresses interleukin-6 (IL-6) production in lipopolysaccharide (LPS, a stimulant of TLR4)-stimulated macrophages of RAGE-knockout mice. In addition, trimebutine suppresses the LPS-induced production of various proinflammatory cytokines and chemokines in mouse macrophage-like RAW264.7 cells. Importantly, trimebutine suppresses IL-6 production induced by TLR2-and TLR7/8/9 stimulants. Furthermore, trimebutine greatly reduces mortality in a mouse model of LPS-induced sepsis. Studies exploring the action mechanism of trimebutine revealed that it inhibits the LPS-induced activation of IL-1 receptor-associated kinase 1 (IRAK1), and the subsequent activations of extracellular signal-related kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and nuclear factor-κB (NF-κB). These findings suggest that trimebutine exerts anti-inflammatory effects on TLR signaling by downregulating IRAK1‒ERK1/2‒JNK pathway and NF-κB activity, thereby indicating the therapeutic potential of trimebutine in inflammatory diseases. Therefore, trimebutine can be a novel anti-inflammatory drug-repositioning candidate and may provide an important scaffold for designing more effective dual anti-inflammatory drugs that target TLR/RAGE signaling.

Keywords

Inflammation; Macrophage; Receptor for advanced glycation end-products; Sepsis; Toll-like receptor; Trimebutine.

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