Arid5a exacerbates IFN-γ-mediated septic shock by stabilizing T-bet mRNA.
Arid5a exacerbates IFN-γ-mediated septic shock by stabilizing T-bet mRNA.
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Arid5a 通过稳定 T-bet mRNA 加剧 IFN-γ 介导的感染性休克。
DOI：
10.1073/pnas.1613307113
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
Kishimoto T.
中科院分区：
文献类型：
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作者：
Zaman MM;Masuda K;Nyati KK;Dubey PK;Ripley B;Wang K;Chalise JP;Higa M;Hanieh H;Kishimoto T.
富含腺嘌呤胸腺嘧啶 (AT) 的相互作用结构域蛋白 5a (Arid5a) 是一种 RNA 结合蛋白，已被证明通过稳定 IL-6 和 STAT3 mRNA 发挥重要的免疫调节功能。然而，Arid5a 在导致感染性休克的压倒性且不受控制的免疫反应中的作用尚不清楚。在这里，我们报告说，Arid5a 缺陷小鼠对脂多糖 (LPS) 诱导的内毒素休克具有高度抵抗力，并且与 WT 小鼠相比，对 LPS 的反应会分泌较低水平的主要促炎细胞因子，包括 IFN-γ、IL-6 和 TNF-α。 Arid5a缺陷导致Th1细胞条件下IFN-γ水平降低，其中T细胞中表达的T-box（T-bet）mRNA表达受到抑制。 Arid5a 与 T-bet 3'UTR 的保守茎环结构结合并稳定其 mRNA。 Arid5a 缺陷小鼠也对痤疮丙酸杆菌引发的 LPS 注射有抵抗力，这被认为是 T 细胞介导的 IFN-γ 依赖性内毒素休克小鼠模型。因此，Arid5a 通过稳定 Th1 细胞中的 T-bet mRNA 来调节 IFN-γ，有助于小鼠感染性休克的发生。此外，我们之前的研究表明，Arid5a 通过稳定 IL-6 mRNA 来响应 LPS 来控制体内 IL-6 水平。我们还观察到，中和 IFN-γ 和 IL-6 可以显着使小鼠从内毒素休克中恢复。综上所述，我们得出结论，Arid5a 调节 LPS 反应中 IL-6 和 IFN-γ 的增强，这可能协同作用以放大各种其他细胞因子，最终导致小鼠发生感染性休克。
Adenine-thymine (AT)-rich interactive domain containing protein 5a (Arid5a) is an RNA-binding protein that has been shown to play an important immune regulatory function via the stabilization of IL-6 and STAT3 mRNA. However, the role of Arid5a in the overwhelming and uncontrolled immune response that leads to septic shock is unknown. Here, we report that Arid5a-deficient mice are highly resistant to lipopolysaccharide (LPS)-induced endotoxic shock and secrete lower levels of major proinflammatory cytokines, including IFN-γ, IL-6, and TNF-α, than WT mice in response to LPS. Arid5a deficiency resulted in decreased levels of IFN-γ under Th1 cell conditions, in which T-box expressed in T cells (T-bet) mRNA expression was inhibited. Arid5a bound to the conserved stem loop structure of the 3′UTR of T-bet and stabilized its mRNA. Arid5a-deficient mice were also resistant toPropionibacterium acnes-primed LPS injection, which is considered to be a T-cell–mediated IFN-γ dependent endotoxic shock mouse model. Thus, regulation of IFN-γ by Arid5a via the stabilization of T-bet mRNA in Th1 cells contributes to the development of septic shock in mice. In addition, our previous study suggests that Arid5a control the IL-6 level in vivo in response to LPS by stabilization of IL-6 mRNA. We also observed that neutralization of IFN-γ and IL-6 significantly recovered the mice from endotoxic shock. Taken together, we conclude that Arid5a regulates the augmentation of IL-6 and IFN-γ in response to LPS, which possibly works synergistically for amplification of various other cytokines that ultimately cause the development of septic shock in mice.