IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
IL-6 Trans-Signaling Modulates TLR4-Dependent Inflammatory Responses via STAT3
复制标题
DOI：
10.4049/jimmunol.1002971
复制
发表时间：
2011-01-15
影响因子：
4.4
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
--
作者：
Greenhill, Claire J.;Rose-John, Stefan;Jenkins, Brendan J.
由原型炎性刺激物LPS触发的先天免疫应答由TLR 4介导，并且涉及多种炎性介质的协调产生，特别是IL-6，其通过共享的IL-6细胞因子家族受体亚基gp 130发出信号。然而，IL-6在TLR 4驱动的炎症性疾病的发病机制中的确切作用，以及IL-6在促炎状态下激活的信号通路的身份，仍然不清楚，IL-6可以引发促炎或抗炎反应。为了确定gp 130信号传导事件对TLR 4驱动的炎症反应的贡献，我们结合了遗传和治疗方法，基于一系列gp 130（F/F）敲入突变小鼠，这些小鼠在LPS/TLR 4的实验模型中表现出超活化的IL-6依赖性JAK/STAT信号传导介导的感染性休克。gp 130（F/F）小鼠对LPS明显过敏，这与IL-6的特异性上调产生有关，但与TNF-α无关。在gp 130（F/F）小鼠中，IL-6的基因消融、Ab介导的IL-6 R信号传导抑制或IL-6反式信号传导的治疗性阻断完全保护小鼠免受LPS超敏反应。此外，gp 130（F/F）：Stat 3（+/-）小鼠中STAT 3活性的遗传降低减轻了LPS超敏性并减少了LPS诱导的IL-6产生。另外的遗传学方法表明，TLR 4/Mal途径有助于LPS超敏反应并增加gp 130（F/F）小鼠中的IL-6产生。总的来说，据我们所知，这些数据第一次证明，通过STAT 3的IL-6反式信号传导是通过TLR 4/Mal信号传导途径的串扰调节的LPS驱动的促炎反应的关键调节剂，并且潜在地暗示JAK/STAT和TLR途径之间的串扰是调节宿主炎症反应的严重性的更广泛机制。免疫学杂志，2011，186：1199-1208。
Innate immune responses triggered by the prototypical inflammatory stimulus LPS are mediated by TLR4 and involve the coordinated production of a multitude of inflammatory mediators, especially IL-6, which signals via the shared IL-6 cytokine family receptor subunit gp130. However, the exact role of IL-6, which can elicit either proinflammatory or anti-inflammatory responses, in the pathogenesis of TLR4-driven inflammatory disorders, as well as the identity of signaling pathways activated by IL-6 in a proinflammatory state, remain unclear. To define the contribution of gp130 signaling events to TLR4-driven inflammatory responses, we combined genetic and therapeutic approaches based on a series of gp130(F/F) knock-in mutant mice displaying hyperactivated IL-6-dependent JAK/STAT signaling in an experimental model of LPS/TLR4-mediated septic shock. The gp130(F/F) mice were markedly hypersensitive to LPS, which was associated with the specific upregulated production of IL-6, but not TNF-alpha. In gp130(F/F) mice, either genetic ablation of IL-6, Ab-mediated inhibition of IL-6R signaling or therapeutic blockade of IL-6 trans-signaling completely protected mice from LPS hypersensitivity. Furthermore, genetic reduction of STAT3 activity in gp130(F/F):Stat3(+/-) mice alleviated LPS hypersensitivity and reduced LPS-induced IL-6 production. Additional genetic approaches demonstrated that the TLR4/Mal pathway contributed to LPS hypersensitivity and increased IL-6 production in gp130(F/F) mice. Collectively, these data demonstrate for the first time, to our knowledge, that IL-6 trans-signaling via STAT3 is a critical modulator of LPS-driven proinflammatory responses through cross-talk regulation of the TLR4/Mal signaling pathway, and potentially implicate cross-talk between JAK/STAT and TLR pathways as a broader mechanism that regulates the severity of the host inflammatory response. The Journal of Immunology, 2011, 186: 1199-1208.