促炎细胞因子
TLR4型
信号转导
愤怒(情绪)
TLR7型
Toll样受体
趋化因子
药理学
激酶
TLR2型
受体
炎症
医学
细胞生物学
免疫学
生物
先天免疫系统
内科学
神经科学
作者
Naomi Ogawa,Shingo Nakajima,Kenya Tamada,Natsuki Yokoue,Haruki Tachibana,Miwa Okazawa,Takahiro Oyama,Hideaki Abe,Hiroaki Yamazaki,Atsushi Yoshimori,Akira Sato,Tomoyasu Kamiya,Takehiko Yokomizo,Fumiaki Uchiumi,Takehiko Abe,Sei Ichi Tanuma
标识
DOI:10.1016/j.abb.2021.109029
摘要
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.
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