活性氧激活的丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK/ERK）通路调节核因子E2相关因子2（Nrf2）和低氧诱导因子-1α（Hif-1α）之间的相互作用，以促进白细胞介素-17D（IL-17D）的表达，从而在高氧环境下保护肠道上皮屏障。
ROS-activated MAPK/ERK pathway regulates crosstalk between Nrf2 and Hif-1α to promote IL-17D expression protecting the intestinal epithelial barrier under hyperoxia.
作者信息
Wang Pingchuan, Li Tianming, Niu Changping, Sun Siyu, Liu Dongyan
机构信息
ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China.
ShengJing Hospital of China Medical University, Department of Gastroenterology, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China.
出版信息
Int Immunopharmacol. 2023 Mar;116:109763. doi: 10.1016/j.intimp.2023.109763. Epub 2023 Feb 1.
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
活性氧（ROS）对肠道屏障的损伤是新生儿长时间高氧治疗的副作用，这会损害肠道的生长和发育并促进肠道疾病。然而，临床防治方面的研究尚缺。因此，我们研究了新生儿肠道对高氧衍生ROS反应的分子机制，以寻找预防肠道屏障损伤的靶点。将人肠上皮细胞置于高氧（85%氧气）条件下孵育以构建体外模型。抑制ROS和丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）通路，检测MAPK/ERK通路、核因子红细胞2相关因子2（Nrf2）、缺氧诱导因子-1α（Hif-1α）和白细胞介素-17D（IL-17D）的表达。抑制Nrf2以检测Hif-1α和IL-17D的表达。抑制Hif-1α以检测Nrf2、IL-17D和紧密连接蛋白的表达及细胞凋亡。用人重组IL-17D处理细胞以检测肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、白细胞介素-10（IL-10）和紧密连接蛋白的表达。高氧条件下ROS、Nrf2、Hif-1α和IL-17D上调，MAPK/ERK通路被激活。但抑制ROS可下调MAPK/ERK通路、Nrf2、Hif-1α和IL-17D。抑制MAPK/ERK通路可下调Nrf2、Hif-1α和IL-17D。抑制Nrf2可下调Hif-1α和IL-17D。抑制Hif-1α可下调Nrf2、IL-17D、紧密连接蛋白并加剧细胞凋亡。重组IL-17D可下调TNF-α、IL-1β，但上调IL-10和紧密连接蛋白。我们得出结论，高氧产生的ROS激活MAPK/ERK通路以调节Nrf2、Hif-1α和IL-17D的表达。Nrf2和Hif-1α相互依赖并促进IL-17D。重要的是，Hif-1α和IL-17D的表达保护肠上皮屏障。
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