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.

由于 Toll 样受体 (TLR) 和晚期糖基化终末产物 (RAGE) 受体在各种急性和慢性炎症性疾病的病理生理学中的关键作用，人们不断努力发现 TLR 和 RAGE 的新型治疗抑制剂，治疗炎症性疾病。我们小组最近的一项研究表明，曲美布汀是一种解痉药物，可抑制与触发巨噬细胞促炎信号通路相关的高迁移率族框 1-RAGE 信号。我们目前的工作表明，曲美布汀抑制 RAGE 基因敲除小鼠的脂多糖（LPS，一种 TLR4 兴奋剂）刺激的巨噬细胞中白细胞介素 6 (IL-6) 的产生。此外，曲美布汀抑制 LPS 诱导的小鼠巨噬细胞样 RAW264.7 细胞中各种促炎细胞因子和趋化因子的产生。重要的是，曲美布汀抑制由 TLR2 和 TLR7/8/9 兴奋剂诱导的 IL-6 产生。此外，曲美布汀大大降低了 LPS 诱导的败血症小鼠模型的死亡率。探索曲美布汀作用机制的研究表明，它抑制 LPS 诱导的 IL-1 受体相关激酶 1 (IRAK1) 的激活，以及随后的细胞外信号相关激酶 1/2 (ERK1/2)、c- Jun N-末端激酶 (JNK) 和核因子-κB (NF-κB)。这些发现表明曲美布汀通过下调 IRAK1-ERK1/2-JNK 通路和 NF-κB 活性对 TLR 信号传导发挥抗炎作用，从而表明曲美布汀在炎症性疾病中的治疗潜力。因此，曲美布汀可以成为一种新型的抗炎药物重新定位候选物，并可能为设计更有效的靶向 TLR/RAGE 信号的双重抗炎药物提供重要的支架。