Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis
Stat2 loss leads to cytokine-independent, cell-mediated lethality in LPS-induced sepsis
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DOI：
10.1073/pnas.1221652110
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发表时间：
2013-05-21
影响因子：
11.1
通讯作者：
Foster, Graham R.
中科院分区：
文献类型：
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作者：
Alazawi, William;Heath, Helen;Foster, Graham R.
失调的 Toll 样受体 (TLR) 引发的依赖 NF-κ B 的炎症反应会过量产生促炎细胞因子（包括 TNF-α），从而对宿主有害。 Stat2 是 I 型 IFN 信号传导的重要组成部分，但不认为它参与 TLR 信号传导。我们的研究表明，LPS 诱导的 Stat2(-/-) 小鼠致死率因细胞迁移增加而加速。阻断细胞间粘附分子-1 可防止细胞流出并赋予 Stat2(-/-) 小鼠生存能力。 Stat2(-/-) 小鼠细胞排出的主要决定因素是宿主的基因型，而不是循环白细胞。令人惊讶的是，在 Stat2(-/-) 小鼠上观察到的致死率和细胞排出与经典脓毒症细胞因子或趋化因子的过度增加无关。事实上，在缺乏 Stat2 的情况下，多种 TLR 激动剂产生的细胞因子产生会减少。我们发现 Stat2 丢失通过影响 NF-kappa B 的核易位导致 NF-kappa B 靶基因表达减少。因此，我们的数据揭示了 LPS 诱导致死的不同机制的存在，该机制独立于 NF-kappa B 触发的细胞因子风暴，但依赖于细胞出口。
Deregulated Toll-like receptor (TLR)-triggered inflammatory responses that depend on NF-kappa B are detrimental to the host via excessive production of proinflammatory cytokines, including TNF-alpha. Stat2 is a critical component of type I IFN signaling, but it is not thought to participate in TLR signaling. Our study shows that LPS-induced lethality in Stat2(-/-) mice is accelerated as a result of increased cellular transmigration. Blocking intercellular adhesion molecule-1 prevents cellular egress and confers survival of Stat2(-/-) mice. The main determinant of cellular egress in Stat2(-/-) mice is the genotype of the host and not the circulating leukocyte. Surprisingly, lethality and cellular egress observed on Stat2(-/-) mice are not associated with excessive increases in classical sepsis cytokines or chemokines. Indeed, in the absence of Stat2, cytokine production in response to multiple TLR agonists is reduced. We find that Stat2 loss leads to reduced expression of NF-kappa B target genes by affecting nuclear translocation of NF-kappa B. Thus, our data reveal the existence of a different mechanism of LPS-induced lethality that is independent of NF-kappa B triggered cytokine storm but dependent on cellular egress.