Complement Activation Product C5a Is a Selective Suppressor of TLR4-Induced, but Not TLR3-Induced, Production of IL-27(p28) from Macrophages
Complement Activation Product C5a Is a Selective Suppressor of TLR4-Induced, but Not TLR3-Induced, Production of IL-27(p28) from Macrophages
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DOI：
10.4049/jimmunol.1102914
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发表时间：
2012-05-15
影响因子：
4.4
通讯作者：
Ward, Peter A.
中科院分区：
文献类型：
--
作者：
Bosmann, Markus;Haggadone, Mikel D.;Ward, Peter A.
越来越多的证据表明，补体激活产物C5 a可以协调细胞免疫功能。IL-27（p28/EBI 3）是一种新兴的关键参与者，对调节炎症反应和T细胞至关重要。在这篇文章中，我们报告，C5 a强烈抑制IL-27（p28）基因的表达和释放在腹腔巨噬细胞。这些来自C57 BL/6 J小鼠的细胞在与TLR 3（聚肌苷酸-聚胞苷酸）或TLR 4（LPS）受体接合后大量产生IL-27（p28）。TLR 4或LBP的遗传缺陷完全使巨噬细胞响应于LPS分泌IL-27（p28）的能力丧失。产生IL-27（p28）的巨噬细胞也表达C5 aR受体，因此显示IL-27（p28）（+）F4/80（+）C5 aR（+）表型。C5 a通过与C5 aR受体而不是C5 L2受体的相互作用抑制LPS刺激的巨噬细胞中的IL-27（p28）。内毒素血症后，C5 aR（-/-）小鼠与C57 BL/6 J小鼠相比显示出更高的血浆IL-27（p28）水平。C5 a不影响IL-27（p28）的释放或IL-27（p28）（+）F4/80（+）巨噬细胞在TLR 3参与后的频率。从机制上讲，LPS激活NF-κ B和PI 3 K/Akt通路，而C5 a仅激活PI 3 K/Akt通路。PI 3 K/Akt的参与抑制IL-27（p28）的产生，因为PI 3 K/Akt药理学阻断导致IL-27（p28）的量增加并逆转C5 a的抑制作用。内毒素血症C57 BL/6 J小鼠中PI 3 K/Akt的阻断导致更高的IL-27（p28）产生。相反，PI 3 K/Akt通路不参与TLR 3介导的IL-27（p28）的释放。这些数据提供了关于补体激活如何在细菌（TLR 4途径）或病毒（TLR 3途径）感染的不同情况下选择性地干扰APC产生T细胞调节性细胞因子的新证据。免疫学杂志，2012，188：5086-5093。
There is accumulating evidence that the complement activation product, C5a, can orchestrate cellular immune functions. IL-27 (p28/EBI3) is an emerging key player essential for regulating inflammatory responses and T cells. In this article, we report that C5a robustly suppressed IL-27(p28) gene expression and release in peritoneal macrophages. These cells from C57BL/6J mice abundantly produced IL-27(p28) after engagement of either the TLR3 (polyinosinic-polycytidylic acid) or TLR4 (LPS) receptor. Genetic deficiency of either TLR4 or LBP Completely incapacitated the ability of macrophages to secrete IL-27(p28) in response to LPS. IL-27(p28) producing macrophages also expressed the C5aR receptor, thus displaying an IL-27(p28)(+)F4/80(+)C5aR(+) phenotype. C5a suppressed IL-27(p28) in LPS-stimulated macrophages via interactions with the C5aR receptor rather than the C5L2 receptor. After endotoxemia, C5aR(-/-) mice displayed higher plasma levels of IL-27(p28) compared with C57BL/6J mice. C5a did not affect the release of IL-27(p28) or the frequency of IL-27(p28)(+)F4/80(+) macrophages after engagement of TLR3. Mechanistically, LPS activated both the NF-kappa B and the PI3K/Akt pathways, whereas C5a activated only the PI3K/Akt pathway. Engagement of PI3K/Akt was inhibitory for IL-27(p28) production, because PI3K/Akt pharmacologic blockade resulted in increased amounts of IL-27(p28) and reversed the suppressive effects of C5a. Blockade of PI3K/Akt in endotoxemic C57BL/6J mice resulted in higher generation of IL-27(p28). In contrast, the PI3K/Akt pathway was not involved in TLR3-mediated release of IL-27(p28). These data provide new evidence about how complement activation may selectively interfere with production of T cell regulatory cytokines by APCs in the varying contexts of either bacterial (TLR4 pathway) or viral (TLR3 pathway) infection. The Journal of Immunology, 2012, 188: 5086-5093.