MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional toll/IL-1 receptor domain/BB-loop mimetics
MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional toll/IL-1 receptor domain/BB-loop mimetics
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DOI：
10.1073/pnas.0510802103
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发表时间：
2006-02-21
影响因子：
11.1
通讯作者：
Bartfai, T
中科院分区：
文献类型：
--
作者：
Davis, CN;Mann, E;Bartfai, T
白细胞介素 (IL)-1 beta 是一种多能促炎细胞因子，通过 I 型 IL-1 受体 (IL-1RI)（Toll 样受体家族的成员）发出信号。在下丘脑神经元中，IL-1β 与 IL-1RI 的结合介导转录依赖性变化，这些变化取决于胞质接头蛋白骨髓分化初级反应蛋白 88 (MyD88) 通过同聚 Toll/IL-1 受体 (TIR)-TIR 募集到 IL-1RI/IL-1 受体辅助蛋白 (IL-1RAcP) 复合物 互动。通过设计和合成破坏 MyD88 与 IL-1RI/IL-1RAcP 复合物相互作用的双功能 Till 模拟物，我们分析了 MyD88 在下丘脑前部神经元 IL-1 β 信号传导中的参与。我们在此表明 IL-1 β 介导的蛋白酪氨酸激酶 Src 激活依赖于 MyD88 与 IL-1RI/IL-1RAcP 复合物的相互作用。蛋白激酶 Akt/PKB 的激活取决于 PI3K 的 p85 亚基向 IL-1RI 的募集，并且独立于 MyD88 与 IL-1RI/IL-1RAcP 复合物的关联。这些双功能 TIR-TIR 模拟物代表了一类具有抗炎和神经保护潜力的低分子量化合物。这些化合物有可能抑制 IL-1 beta 的 MyD88 依赖性促炎作用，同时允许由不依赖 MyD88 的蛋白激酶 Akt 激活介导的潜在神经元存活支持作用。
Interleukin (IL)-1 beta is a pluripotent proinflammatory cytokine that signals through the type-I IL-1 receptor (IL-1RI), a member of the Toll-like receptor family. In hypothalamic neurons, binding of IL-1 beta to IL-1RI mediates transcription-dependent changes that depend on the recruitment of the cytosolic adaptor protein myeloid differentiation primary-response protein 88 (MyD88) to the IL-1RI/IL-1 receptor accessory protein (IL-1RAcP) complex through homomeric Toll/IL-1 receptor (TIR)-TIR interactions. Through design and synthesis of bifunctional Till mimetics that disrupt the interaction of MyD88 with the IL-1RI/IL-1RAcP complex, we analyzed the involvement of MyD88 in the signaling of IL-1 beta in anterior hypothalamic neurons. We show here that IL-1 beta-mediated activation of the protein tyrosine kinase Src depended on a MyD88 interaction with the IL-1RI/IL-1RAcP complex. The activation of the protein kinase Akt/PKB depended on the recruitment of the p85 subunit of PI3K to IL-1RI and independent of MyD88 association with the IL-1RI/IL-1RAcP complex. These bifunctional TIR-TIR mimetics represent a class of low-molecular-Weight compounds with both an antiinflammatory and neuroprotective potential. These compounds have the potential to inhibit the MyD88-dependent proinflammatory actions of IL-1 beta, while permitting the potential neuronal survival supporting actions mediated by the MyD88-independent activation of the protein kinase Akt.