Takada Yoko K, Takada Yoshikazu
Department of Dermatology, University of California School of Medicine, Research III Suite 3300, 4645 Second Ave., Sacramento, CA 95817, USA.
Department of Biochemistry and Molecular Medicine, University of California School of Medicine, Research III Suite 3300, 4645 Second Ave., Sacramento, CA 95817, USA.
Int J Mol Sci. 2025 Sep 5;26(17):8655. doi: 10.3390/ijms26178655.
Ivermectin (IVM), a broad-spectrum anthelmintic agent, has anti-inflammatory properties, and affects cellular and humoral immune responses. We recently showed that multiple pro-inflammatory cytokines (e.g., FGF2, CCL5, CD40L) bind to the allosteric site (site 2) of integrins and activate them. 25-Hydroxycholesterol, a pro-inflammatory lipid mediator, is known to bind to site 2 and induce integrin activation and inflammatory signals (e.g., IL-6 and TNF secretion), suggesting that site 2 is critically involved in inflammation. We showed that two anti-inflammatory cytokines (FGF1 and NRG1) bind to site 2 and inhibit integrin activation by inflammatory cytokines. We hypothesized that ivermectin binds to site 2 and inhibits inflammatory signaling by pro-inflammatory cytokines. A docking simulation predicts that ivermectin binds to site 2. Ivermectin inhibits the integrin activation induced by inflammatory cytokines, suggesting that ivermectin is a site 2 antagonist. We showed that TNF, a major pro-inflammatory cytokine, binds to integrin site 2 and induces allosteric integrin activation like other pro-inflammatory cytokines, suggesting that site 2 binding and integrin activation is a potential mechanism of the pro-inflammatory action of these cytokines. Ivermectin suppressed the activation of soluble β3 integrins by TNF and other pro-inflammatory cytokines in a dose-dependent manner in cell-free conditions. Binding to site 2 and the inhibition of binding of inflammatory cytokines may be a potential mechanism of anti-inflammatory action of ivermectin.
伊维菌素（IVM）是一种广谱驱虫剂，具有抗炎特性，并影响细胞免疫和体液免疫反应。我们最近发现多种促炎细胞因子（如FGF2、CCL5、CD40L）与整合素的变构位点（位点2）结合并激活它们。25-羟基胆固醇是一种促炎脂质介质，已知其与位点2结合并诱导整合素激活和炎症信号（如IL-6和TNF分泌），这表明位点2在炎症中起关键作用。我们发现两种抗炎细胞因子（FGF1和NRG1）与位点2结合并抑制促炎细胞因子介导的整合素激活。我们推测伊维菌素与位点2结合并抑制促炎细胞因子的炎症信号传导。对接模拟预测伊维菌素与位点2结合。伊维菌素抑制炎症细胞因子诱导的整合素激活，这表明伊维菌素是一种位点2拮抗剂。我们发现，主要促炎细胞因子TNF与整合素位点2结合，并像其他促炎细胞因子一样诱导变构整合素激活，这表明位点2结合和整合素激活是这些细胞因子促炎作用的潜在机制。在无细胞条件下，伊维菌素以剂量依赖的方式抑制TNF和其他促炎细胞因子对可溶性β3整合素的激活。与位点2结合以及抑制炎症细胞因子的结合可能是伊维菌素抗炎作用的潜在机制。
