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Nrf2/HO-1 partially regulates cytoprotective effects of carbon monoxide against urban particulate matter-induced inflammatory responses in oral keratinocytes
Cytokine ( IF 3.8 ) Pub Date : 2020-09-01 , DOI: 10.1016/j.cyto.2020.155185
Ching-Yi Cheng , Thi Thuy Tien Vo , Wei-Ning Lin , Hsiang-Wei Huang , Chu-Chun Chuang , Pei-Ming Chu , I-Ta Lee

INTRODUCTION Exposure to airborne particulate matter (PM) increases the proportion of oral inflammatory diseases. During the formation of inflammatory conditions, the nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome activation plays an important regulator. Carbon monoxide (CO) arising from heme degradation, catalyzed particularly by heme oxygenase-1 (HO-1), has been shown to own cytoprotective effects including anti-inflammation and antioxidant. Here, we determined the novel mechanisms of carbon monoxide releasing molecule-2 (CORM-2) on PM-induced inflammatory responses in human oral keratinocytes (HOKs). METHODS The effects of CORM-2 on the expression of various inflammatory proteins induced by PM were determined by Western blot, real-time PCR, promoter assay, and ELISA. The involvement of signaling molecules in these responses was studied by using the selective pharmacological inhibitors and siRNAs. RESULTS We proved that PM enhanced C-reactive protein (CRP) levels, NLRP3 inflammasome and caspase-1 activation, and IL-1β release, which were reduced by preincubation with CORM-2. Transfection with PKCα siRNA and preincubation with the ROS scavenger (N-acetyl-cysteine, NAC), an inhibitor of NADPH oxidase (diphenyleneiodonium, DPI), or the mitochondria-specific superoxide scavenger (MitoTEMPO) inhibited PM-mediated inflammatory responses. In addition, PM-regulated PKCα and NADPH oxidase activation as well as NADPH oxidase- and mitochondria-derived ROS generation were inhibited by CORM-2, but not inactivate CORM-2 (iCORM-2) pretreatment. At the end, we confirmed that CORM-2 improved PM-induced inflammatory responses via the induction of Nrf2 activation and HO-1 expression. CONCLUSION We suggest that CORM-2 inhibits PM-induced inflammatory responses in HOKs via the inhibition of PKCα/ROS/NLRP3 inflammasome activation combined with the induction of Nrf2/HO-1 expression.

中文翻译:

Nrf2/HO-1 部分调节一氧化碳对城市颗粒物诱导的口腔角质形成细胞炎症反应的细胞保护作用

介绍 暴露于空气中的颗粒物 (PM) 会增加口腔炎症性疾病的比例。在炎症条件的形成过程中,核苷酸结合域和富含亮氨酸的重复蛋白 3 (NLRP3) 炎症小体激活起着重要的调节作用。由血红素降解产生的一氧化碳 (CO),特别是由血红素加氧酶-1 (HO-1) 催化,已被证明具有细胞保护作用,包括抗炎和抗氧化。在这里,我们确定了一氧化碳释放分子 2 (CORM-2) 对 PM 诱导的人口腔角质形成细胞 (HOKs) 炎症反应的新机制。方法采用Western blot、实时荧光定量PCR、启动子试验和ELISA等方法检测CORM-2对PM诱导的多种炎症蛋白表达的影响。通过使用选择性药理学抑制剂和 siRNAs 研究了信号分子在这些反应中的参与。结果 我们证明 PM 增强了 C 反应蛋白 (CRP) 水平、NLRP3 炎症小体和 caspase-1 激活以及 IL-1β 释放,这些都通过与 CORM-2 预孵育而减少。转染 PKCα siRNA 并与 ROS 清除剂(N-乙酰-半胱氨酸,NAC)、NADPH 氧化酶抑制剂(二亚苯基碘,DPI)或线粒体特异性超氧化物清除剂 (MitoTEMPO) 进行预培养,可抑制 PM 介导的炎症反应。此外,PM 调节的 PKCα 和 NADPH 氧化酶激活以及 NADPH 氧化酶和线粒体衍生的 ROS 生成被 CORM-2 抑制,但不会使 CORM-2 (iCORM-2) 预处理失活。在末尾,我们证实 CORM-2 通过诱导 Nrf2 激活和 HO-1 表达改善 PM 诱导的炎症反应。结论 我们认为 CORM-2 通过抑制 PKCα/ROS/NLRP3 炎性体激活结合诱导 Nrf2/HO-1 表达来抑制 HOK 中 PM 诱导的炎症反应。
更新日期:2020-09-01
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