Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro-inflammatory cytokines
Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro-inflammatory cytokines
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表皮生长因子受体信号的激活介导某些促炎细胞因子诱导的细胞衰老
DOI：
10.1111/acel.13145
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发表时间：
2020
期刊：
影响因子：
7.8
通讯作者：
Tu Zhigang
中科院分区：
文献类型：
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作者：
Shang Dongsheng;Sun Danlin;Shi Chunyan;Xu Jun;Shen Mingxiang;Hu Xing;Liu Hanqing;Tu Zhigang
众所周知，体内炎症会促进机体衰老，最近的研究也将类似的效应归因于衰老细胞。考虑到某些促炎细胞因子可以诱导细胞衰老，系统评估促炎细胞因子在细胞衰老中的作用是一个重要而紧迫的科学问题，特别是考虑到人口老龄化的持续激增。用促炎细胞因子处理 IMR90 细胞和 HUVEC 发现了六种能够有效诱导细胞衰老的因素。在这些衰老诱导细胞因子中，有 5 种细胞因子（即 IL-1β、IL-13、MCP-2、MIP-3α 和 SDF-1α）的活性通过西妥昔单抗（一种靶向表皮生长因子受体 [EGFR] 的抗体）、吉非替尼（EGFR 小分子抑制剂）和 EGFR 敲除治疗显着抑制。此外，用一种衰老诱导细胞因子 SDF-1α 治疗可显着增加 EGFR 以及 Erk1/2 的磷酸化水平。这些结果表明促炎细胞因子通过激活 EGFR 信号传导诱导细胞衰老。接下来，我们发现EGF治疗还可以诱导IMR90细胞和HUVEC的细胞衰老。从机械角度来说，EGF 通过过度激活 Ras 和 Ras-BRaf-Erk1/2 信号轴来诱导细胞衰老。此外，EGFR 激活诱导 IMR90 细胞分泌某些衰老相关的分泌表型因子（IL-8 和 MMP-3）。总之，我们报告某些促炎细胞因子通过激活 EGFR-Ras 信号通路诱导细胞衰老。因此，我们的研究为 EGFR 调节细胞衰老的长期被忽视的机制提供了新的见解，并表明生长信号本身可能在某些条件下催化衰老。
It is well established that inflammation in the body promotes organism aging, and recent studies have attributed a similar effect to senescent cells. Considering that certain pro‐inflammatory cytokines can induce cellular senescence, systematically evaluating the effects of pro‐inflammatory cytokines in cellular senescence is an important and urgent scientific problem, especially given the ongoing surge in aging human populations. Treating IMR90 cells and HUVECs with pro‐inflammatory cytokines identified six factors able to efficiently induce cellular senescence. Of these senescence‐inducing cytokines, the activity of five (namely IL‐1β, IL‐13, MCP‐2, MIP‐3α, and SDF‐1α) was significantly inhibited by treatment with cetuximab (an antibody targeting epidermal growth factor receptor [EGFR]), gefitinib (a small molecule inhibitor of EGFR), and EGFR knockdown. In addition, treatment with one of the senescence‐inducing cytokines, SDF‐1α, significantly increased the phosphorylation levels of EGFR, as well as Erk1/2. These results suggested that pro‐inflammatory cytokines induce cellular senescence by activating EGFR signaling. Next, we found that EGF treatment could also induce cellular senescence of IMR90 cells and HUVECs. Mechanically, EGF induced cellular senescence via excessive activation of Ras and the Ras‐BRaf‐Erk1/2 signaling axis. Moreover, EGFR activation induced IMR90 cells to secrete certain senescence‐associated secretory phenotype factors (IL‐8 and MMP‐3). In summary, we report that certain pro‐inflammatory cytokines induce cellular senescence through activation of the EGFR‐Ras signaling pathway. Our study thus offers new insight into a long‐ignored mechanism by which EGFR could regulate cellular senescence and suggests that growth signals themselves may catalyze aging under certain conditions.