Discipline of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, 453552 Indore, MP, India.
Discipline of Chemistry, School of Basic Sciences, Indian Institute of Technology Indore (IITI), Simrol, 453552 Indore, MP, India.
Int Immunopharmacol. 2019 Jun;71:188-197. doi: 10.1016/j.intimp.2019.03.031. Epub 2019 Mar 22.
Bacterial endotoxin-induced sepsis causes 30-40% of the deaths in the intensive care unit (ICU) globally, for which there is no pharmacotherapy. Lipopolysaccharide (LPS), a bacterial endotoxin, stimulates the Toll-like receptor (TLR)-4 signalling pathways to upregulate the expression of various inflammatory mediators. Here, we show that the TIRAP and c-Jun protein signalling complex forms in macrophages in response to LPS stimulation, which increases the AP1 transcriptional activity, thereby amplifying the expression of inflammatory mediators. Using a computer-aided molecular docking platform, we identified gefitinib as a putative inhibitor of the TIRAP-c-Jun signalling complex. Further, we demonstrated the ability of gefitinib to inhibit the interaction of TIRAP-c-Jun with in vitro experiments and with a mouse model of sepsis. Importantly, pre-treatment with gefitinib increased the survival of the mice that received a lethal dose of LPS compared to that of the controls. These findings verify the ability of gefitinib to directly disrupt the interaction of TIRAP and c-Jun, thereby inhibiting a major inflammatory response that is often observed in patients experiencing sepsis.
细菌内毒素诱导的脓毒症导致全球重症监护病房（ICU）中 30-40%的患者死亡，但目前尚无有效的药物治疗方法。脂多糖（LPS）是一种细菌内毒素，它通过刺激 Toll 样受体（TLR）-4 信号通路来上调各种炎症介质的表达。在这里，我们发现 TLRAP 和 c-Jun 蛋白信号复合物在巨噬细胞中形成，以响应 LPS 刺激，这增加了 AP1 转录活性，从而放大炎症介质的表达。我们使用计算机辅助分子对接平台鉴定出吉非替尼是 TIRAP-c-Jun 信号复合物的潜在抑制剂。此外，我们还通过体外实验和脓毒症小鼠模型证明了吉非替尼抑制 TIRAP-c-Jun 相互作用的能力。重要的是，与对照组相比，吉非替尼预处理可增加接受致死剂量 LPS 的小鼠的存活率。这些发现验证了吉非替尼能够直接破坏 TIRAP 和 c-Jun 的相互作用，从而抑制脓毒症患者中经常观察到的主要炎症反应。
