The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals
The role of Tyk2, Stat1 and Stat4 in LPS-induced endotoxin signals
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DOI：
10.1093/intimm/dxh118
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发表时间：
2004-08-01
影响因子：
4.4
通讯作者：
Harada, M
中科院分区：
文献类型：
--
作者：
Kamezaki, K;Shimoda, K;Harada, M
缺乏Tyk 2、Stat 1或Stat 4的小鼠对LPS诱导的内毒素休克具有抗性，Tyk 2、Stat 1或Stat 4是Jak-Stat信号级联的成员。有趣的是，Tyk 2缺陷小鼠对LIPS攻击的抵抗力高于缺乏Stat 1或Stat 4的小鼠。LPS对MAPK和NF-κ B的激活，以及LPS注射后TNF-α和IL-12的产生，并没有因为Tyk 2、Stat 1或Stat 41的缺失而消失。在Stat 1缺陷小鼠中，巨噬细胞中LIPS对IFN-β的诱导作用严重降低，尽管LPS注射后IFN-γ的血清水平升高。相比之下，在Stat-4缺陷小鼠中，LIPS对IFN-β的诱导是正常的，但是在LPS注射后IFN-γ的血清水平仍然很低。有趣的是，在Tyk 2缺陷小鼠中，LIPS对IFN-β和IFN-γ的诱导都严重减少。因此，Stat 1和Stat 4独立地在LIPS的易感性中发挥重要作用。Tyk 2是LPS诱导的内毒素休克所必需的，并且该信号通路通过激活Stat 1和Stat 4来转导。
Mice lacking Tyk2, Stat1 or Stat4, which are members of the Jak-Stat signaling cascade, were resistant to LPS-induced endotoxin shock. Interestingly, Tyk2-deficient mice had higher resistance to LIPS challenge than mice lacking either Stat1 or Stat4. The activation of MAPK and NF-kappaB by LIPS, and the production of TNF-alpha and IL-12 after LPS injection, were not abrogated by the absence of Tyk2, Stat1 or Stat4l. In Stat1-deficient mice, the induction of IFN-beta by LIPS in macrophages was severely reduced, although the serum level of IFN-gamma was elevated after LPS injection. In contrast, in Stat-4 deficient mice, the induction of IFN-beta by LIPS was normal, but the serum level of IFN-gamma remained low after LPS injection. Interestingly, the induction of both IFN-beta and IFN-gamma by LIPS was severely reduced in Tyk2-deficient mice. Therefore, Stat1 and Stat4 independently play substantial roles in the susceptibility to LIPS. Tyk2 is essential for LIPS-induced endotoxin shock, and this signaling pathway is transduced by the activation of Stat1 and Stat4.