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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses
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A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses

机译：Toll / IL-1受体/耐药域的低分子量模拟物可抑制IL-1受体介导的反应

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Toll-like receptors (TLRs) and the type I IL-1 receptor (IL-1RI) are key components of the innate immune system activated by microbial infections and inflammation. The signaling cascade from agonist-occupied TLRs and IL-1Rs involves recruitment of the small cytosolic adapter protein MyD88 that binds to IL-1RI via homotypic interactions mediated by Toll/IL-1R/resistance (TIR) domains. Dominant negative forms and null mutations of MyD88 have recently been shown to preclude bacterial product or IL-1-mediated activation of NF-kappaB pathways, demonstrating that MyD88 is an essential component of the Toll receptor signaling. Here, we report the synthesis and pharmacological effects of a low molecular weight MyD88 mimic, hydrocinnamoyl-L-valyl pyrrolidine (compound 4a), modeled on a tripeptide sequence of the BB-loop [(F/Y)-(V/L/I)-(P/G)] of the TIR domain. Results are presented showing that compound 4a interferes with the interactions between mouse MyD88 and IL-1RI at the TIR domains. Compound 4a inhibited IL-1beta-induced phosphorylation of the mitogen-activated protein kinase p38 in EL4 thymoma cells and in freshly isolated murine lymphocytes in a concentration-dependent manner. In vivo, compound 4a produced a significant attenuation of the IL-1beta-induced fever response (200 mg/kg, i.p.). Inhibition of the TIR domain-mediated MyD88/IL1-RI interaction by a low molecular weight, cell-penetrating TIR domain mimic suggests an intracellular site for antiinflammatory drug action. [References: 27]
机译：Toll样受体（TLR）和I型IL-1受体（IL-1RI）是由微生物感染和炎症激活的先天免疫系统的关键组成部分。激动剂占据的TLR和IL-1R的信号级联涉及募集小细胞溶质衔接蛋白MyD88，该蛋白通过Toll / IL-1R /抗性（TIR）域介导的同型相互作用与IL-1RI结合。最近已证明，MyD88的主要阴性形式和无效突变可阻止细菌产物或IL-1介导的NF-κB途径活化，这表明MyD88是Toll受体信号转导的重要组成部分。在这里，我们报告的低分子量MyD88模仿，氢肉桂酰基-L-戊基吡咯烷（化合物4a）的合成和药理作用，仿照BB环的三肽序列[（F / Y）-（V / L / I）-（P / G）]。结果表明化合物4a在TIR域干扰了小鼠MyD88和IL-1RI之间的相互作用。化合物4a以浓度依赖的方式抑制IL4胸腺瘤细胞和新鲜分离的鼠淋巴细胞中IL-1β诱导的丝裂原活化蛋白激酶p38的磷酸化。在体内，化合物4a显着减弱了IL-1β诱导的发烧反应（200mg / kg，腹膜内）。低分子量，穿透细胞的TIR结构域模拟物对TIR结构域介导的MyD88 / IL1-RI相互作用的抑制作用提示细胞内有抗炎药作用位点。 [参考：27]

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