Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
The Department of Anesthesia, Nanfang Hospital, Southern Medical University, Guangzhou, China.
J Cell Physiol. 2018 Sep;233(9):6975-6983. doi: 10.1002/jcp.26488. Epub 2018 Apr 10.
Epithelial growth factor receptor (EGFR), a tyrosine kinase receptor, plays a critical role in lipopolysaccharide (LPS)-induced endotoxemia. Meanwhile, EGFR signaling is regulated by multiple feedback regulators, including mitogen-inducible gene 6 protein (Mig6). However, as an EGFR regulator, the role of Mig6 in endotoxemia is still remained unknown. Here, we reported for the first time that LPS treatment increased the expression of Mig6 and this effect could be inhibited by EGFR inhibitor, PD168393 or erlotinib. Furthermore, knocking down of Mig6 expression led to increased EGFR activation and inflammatory mediators (TNF-α, il-1β) production in response to LPS treatment. On the other hand, the increased EGFR activation and TNF-α or il-1β production in LPS treatment could be inhibited by Mig6 overexpression. Besides, in LPS-induced endotoxemia, ERK1/2 and p-38 activation required Mig6. All these results indicated that Mig6 regulates the production of inflammatory mediators (TNF-α, il-1β) through inhibiting the over activation of EGFR, which in turn inhibit MAPKs signaling (ERK1/2, p-38). These finding suggested that Mig6 may be a novel potential target for controlling the over inflammatory response in endotoxemia.
表皮生长因子受体（EGFR）是一种酪氨酸激酶受体，在脂多糖（LPS）诱导的内毒素血症中发挥关键作用。同时，EGFR 信号受多种反馈调节剂调控，包括有丝分裂原诱导基因 6 蛋白（Mig6）。然而，作为 EGFR 调节剂，Mig6 在内毒素血症中的作用尚不清楚。在这里，我们首次报道 LPS 处理可增加 Mig6 的表达，而 EGFR 抑制剂 PD168393 或厄洛替尼可抑制这种作用。此外，敲低 Mig6 的表达可导致 LPS 处理时 EGFR 激活和炎症介质（TNF-α、il-1β）的产生增加。另一方面，Mig6 的过表达可抑制 LPS 处理时 EGFR 的过度激活和 TNF-α 或 il-1β 的产生。此外，在 LPS 诱导的内毒素血症中，ERK1/2 和 p-38 的激活需要 Mig6。所有这些结果表明，Mig6 通过抑制 EGFR 的过度激活来调节炎症介质（TNF-α、il-1β）的产生，从而抑制 MAPKs 信号（ERK1/2、p-38）。这些发现表明 Mig6 可能是控制内毒素血症过度炎症反应的一个新的潜在靶点。
