IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling
IL-6 Controls the Innate Immune Response against Listeria monocytogenes via Classical IL-6 Signaling
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DOI：
10.4049/jimmunol.1201044
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发表时间：
2013-01-15
影响因子：
4.4
通讯作者：
Mittruecker, Hans-Willi
中科院分区：
文献类型：
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作者：
Hoge, Judith;Yan, Isabell;Mittruecker, Hans-Willi
细胞因子 IL-6 在针对细菌感染的免疫反应中发挥保护作用。然而，IL-6 介导的保护机制尚不完全清楚。 IL-6 可以通过由膜结合 IL-6R α (mIL-6R α) 和 gp130 组成的 IL-6R 复合物发出信号。由于 mIL-6R α 的表达受到限制，经典的 IL-6 信号传导仅发生在有限数量的细胞中，例如肝细胞和某些白细胞亚群。 IL-6 还与可溶性 IL-6R α 蛋白相互作用，这些 IL-6/可溶性 IL-6R α 复合物随后可以与膜结合的 gp130 蛋白结合并诱导信号传导。由于 gp130 普遍表达，这种 IL-6 反式信号传导显着增加了细胞对 IL-6 的反应谱。在本研究中，我们分析了经典 IL-6 信号传导和 IL-6 反式信号传导在小鼠针对单核细胞增生李斯特菌感染的先天免疫反应中的作用。我们证明，单核细胞增多性李斯特菌感染会导致全身性 IL-6 大量产生，并导致中性粒细胞、炎性单核细胞和不同淋巴细胞亚群上的 IL-6R α 表面表达迅速丧失。 IL-6缺陷型小鼠或用中和性抗IL-6 mAb治疗的小鼠表现出对单核细胞增生李斯特菌感染的控制受损，并伴有炎症细胞因子和趋化因子表达以及炎症细胞募集的改变。相反，通过应用可溶性 gp130 蛋白或转基因表达来限制性阻断 IL-6 反式信号传导并不能抑制感染的控制。总之，我们的结果表明，IL-6R α 表面表达在针对单核细胞增生李斯特菌的先天反应过程中是高度动态的，并且保护性 IL-6 功能依赖于通过 mIL-6R α 的经典 IL-6 信号传导。免疫学杂志，2013，190：703-711。
The cytokine IL-6 plays a protective role in immune responses against bacterial infections. However, the mechanisms of IL-6-mediated protection are only partially understood. IL-6 can signal via the IL-6R complex composed of membrane-bound IL-6R alpha (mIL-6R alpha) and gp130. Owing to the restricted expression of mIL-6R alpha, classical IL-6 signaling occurs only in a limited number of cells such as hepatocytes and certain leukocyte subsets. IL-6 also interacts with soluble IL-6R alpha proteins and these IL-6/soluble IL-6R alpha complexes can subsequently bind to membrane-bound gp130 proteins and induce signaling. Because gp130 is ubiquitously expressed, this IL-6 trans-signaling substantially increases the spectrum of cells responding to IL-6. In this study, we analyze the role of classical IL-6 signaling and IL-6 trans-signaling in the innate immune response of mice against Listeria monocytogenes infection. We demonstrate that L. monocytogenes infection causes profound systemic IL-6 production and rapid loss of IL-6R alpha surface expression on neutrophils, inflammatory monocytes, and different lymphocyte subsets. IL-6-deficient mice or mice treated with neutralizing anti-IL-6 mAb displayed impaired control of L. monocytogenes infection accompanied by alterations in the expression of inflammatory cytokines and chemokines, as well as in the recruitment of inflammatory cells. In contrast, restricted blockade of IL-6 trans-signaling by application or transgenic expression of a soluble gp130 protein did not restrain the control of infection. In summary, our results demonstrate that IL-6R alpha surface expression is highly dynamic during the innate response against L. monocytogenes and that the protective IL-6 function is dependent on classical IL-6 signaling via mIL-6R alpha. The Journal of Immunology, 2013, 190: 703-711.