Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance
Synergistic Signaling of TLR and IFNα/β Facilitates Escape of IL-18 Expression from Endotoxin Tolerance
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DOI：
10.1164/rccm.201903-0659oc
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发表时间：
2020-03-01
影响因子：
24.7
通讯作者：
Kessel, Christoph
中科院分区：
文献类型：
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作者：
Verweyen, Emely;Holzinger, Dirk;Kessel, Christoph
理由：IL-18 是 IL-1 细胞因子家族的一员，血液中 IL-18 浓度升高与巨噬细胞活化综合征 (MAS) 的疾病活动以及严重炎症和脓毒症的不良临床结果相关。 目的：虽然最近的研究提供了 IL-18 对脓毒症和 MAS 炎症和过度炎症的作用机制证据，但我们试图研究人类 IL-18 表达的调节机制。 方法：来自体内和体外的样本内毒素再激发实验、炎症性疾病患者以及经各种兴奋剂和药物处理的分离的人单核细胞均被检测细胞因子基因和蛋白质表达。在两种 MAS 小鼠模型和一名复发性 MAS 患者中分析了有或没有 JAK/STAT 抑制的血清 IL-18 表达。测量和主要结果：外周血和单核细胞 IL-18 表达逃脱了 LPS 诱导的免疫麻痹。 LPS 刺激的原代人单核细胞显示出受 IFN α/β 信号传导控制的特定 IL-18 表达动力学。 LPS 刺激期间的 JAK/STAT 抑制或 IFNb 中和会减弱细胞因子的表达。同样，微管不稳定药物消除了 LPS 诱导的 IL18 表达，但这种效应可以通过添加 IFN α/β 来完全逆转。对炎症性疾病患者全血的离体分析显示，I 型 IFN 评分和 IL18 表达之间存在很强的相关性，而 JAK/STAT 抑制则显着降低了两种 MAS 小鼠模型和复发性 MAS 患者的 IL-18 血清水平。结论：我们的数据表明，人类单核细胞产生 IL-18（而非 IL-1β）需要 Toll 样受体和 IFN α/β 信号传导的配合。 JAK/STAT 抑制后干扰 IFN α/β 表达或信号传导可能会控制 MAS 中的灾难性过度炎症。
Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFN alpha/beta signaling. JAK/STAT inhibition or IFNb neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFN alpha/beta. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.Conclusions: Our data indicate that IL-18 (but not IL-1 beta) production from human monocytes requires cooperative Toll-like receptor and IFN alpha/beta signaling. Interference with IFN alpha/beta expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.