Toll-like receptor 4 contributes to uterine activation by upregulating pro-inflammatory cytokine and CAP expression via the NF-κB/P38MAPK signaling pathway during pregnancy
Toll-like receptor 4 contributes to uterine activation by upregulating pro-inflammatory cytokine and CAP expression via the NF-κB/P38MAPK signaling pathway during pregnancy
复制标题
Toll 样受体 4 在妊娠期间通过 NF-κB/P38MAPK 信号通路上调促炎细胞因子和 CAP 表达，有助于子宫激活
DOI：
10.1002/jcp.28991
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Kang, Xiangdong
中科院分区：
文献类型：
--
作者：
Chen, Zixi;Liu, Qiaoli;Kang, Xiangdong
有证据表明，在人类分娩的生理过程中，炎症反应是重要的，然而，触发炎症的具体信号通路尚不清楚。Toll样受体(TLRs)是关键的上游守门人，在早产前控制炎症激活。我们先前的研究表明，TLR4在早产和足月分娩期间妊娠组织中的表达显著增加。因此，我们探讨TLR4是否通过启动炎症反应从而促进子宫激活而在足月分娩中发挥作用。结果表明，足月分娩组与非足月分娩组相比，TLR4、IL-1β、IL-6、肿瘤坏死因子-α(TNF-α)、CC趋化因子配体2(CCL-2)和子宫收缩相关蛋白(CAPS)的表达均上调，且TLR4水平与CAP表达呈正相关。TLR4基因敲除(TLR4(-/-))小鼠与野生型小鼠相比，孕期延长8小时，IL-1β、IL-6、TNF-α、CCL-2和CAPS表达降低。此外，核因子-kappaB和p38MAPK的激活参与了分娩的启动，但在TLR4(-/-)小鼠中受到抑制。在子宫平滑肌细胞中，当抑制NF-kappaB和p38MAPK通路时，炎性细胞因子和CAPS的表达减少。我们的数据表明，TLR4是调节炎症反应的关键因素，炎症反应通过激活NF-kappa B/p38MAPK途径来驱动子宫激活和分娩开始。
Evidence indicates that inflammatory response is significant during the physiological process of human parturition; however, the specific signaling pathway that triggers inflammation is undefined. Toll-like receptors (TLRs) are key upstream gatekeepers that control inflammatory activation before preterm delivery. Our previous study showed that TLR4 expression was significantly increased in human pregnancy tissue during preterm and term labor. Therefore, we explore whether TLR4 plays a role in term labor by initiating inflammatory responses, therefore promoting uterine activation. The results showed that expression of TLR4, interleukin-1 beta (IL-1 beta), IL-6, tumor necrosis factor-alpha (TNF-alpha), CC chemokine ligand 2 (CCL-2), and uterine contraction-associated proteins (CAPs) was upregulated in the human and mice term labor (TL) group compared with the not-in-labor (TNL) group, and the TLR4 level positively correlated with CAP expression. In pregnant TLR4-knockout (TLR4(-/-)) mice, gestation length was extended by 8 hr compared with the wild-type group, and the expression of IL-1 beta, IL-6, TNF-alpha, CCL-2, and CAPs was decreased in TLR4(-/-) mice. Furthermore, nuclear factor-kappa B (NF-kappa B) and P38MAPK activation is involved in the initiation of labor but was inhibited in TLR4(-/-) mice. In uterine smooth muscle cells, the expression of inflammatory cytokines and CAPs decreased when the NF-kappa B and P38MAPK pathway was inhibited. Our data suggest that TLR4 is a key factor in regulating the inflammatory response that drives uterine activation and delivery initiation via activating the NF-kappa B/P38MAPK pathway.