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首页> 外文期刊>Cellular Physiology and Biochemistry >MAPK and JAK-STAT Signaling Pathways are Involved in the Oxidative Stress – Induced Decrease in Expression of Surfactant Protein Genes
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MAPK and JAK-STAT Signaling Pathways are Involved in the Oxidative Stress – Induced Decrease in Expression of Surfactant Protein Genes

机译：MAPK和JAK-STAT信号通路参与氧化应激诱导的表面活性剂蛋白基因表达的减少

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Oxidative stress is generated by reactive oxygen species (ROS) including hydrogen peroxide (Hsub2/subOsub2/sub), hydroxyl radical (?OH ) and superoxide anion (Osup2––/sup), which are produced as by-products of cellular metabolism. An imbalance in cellular redox status is a potent pathogenic factor that contributes to various chronic inflammatory diseases. In this study, we demonstrate that Hsub2/subOsub2 /subdecreases surfactant protein A, B and ABCA3 mRNA level, and increases SP-D mRNA level in human pulmonary lung epithelial cells. The decreased mRNA level of SP-A and SP-B were significant with a maximum inhibition of 79 and 87%, respectively by 150 µM Hsub2/subOsub2 /subafter 24 hrs of incubation. In addition, ABCA3 mRNA level was decreased with a maximum inhibition of 55% by 150 µM Hsub2/subOsub2 /subafter 12 hrs of incubation. In contrast, 150 µM Hsub2/subOsub2 /subcaused the SP-D mRNA level to increase to 200% of control after 8 hrs of incubation. The Hsub2/subOsub2/sub-induced gene repression or activation of SP-A, SP-B, SP-D and ABCA3 was blocked by pretreatment with the antioxidants N-acetyl-L-cysteine (NAC) and catalase. Furthermore, the inhibition of SP-A and SP-B was associated with reduced thyroid transcription factor -1 (TTF-1) DNA binding activity, and this reduced TTF-1 binding activity may be due to decreased TTF-1 protein expression level. The analyses of signal transduction pathways that may play a role in the regulation of gene expression by Hsub2/subOsub2 /subusing several specific inhibitors showed that U0126, an inhibitor of ERK1/2 upstream kinase MEK1/2, blocked both Hsub2/subOsub2/sub-induced inhibition of SP-A and SP-B gene expression, whereas SB203580, an inhibitor of p38 MAPK, partially blocked Hsub2/subOsub2/sub-mediated inhibition of SP-A gene expression but not SP-B expression. In contrast, AG-490, a specific inhibitor of JAK-STAT pathway, blocked Hsub2/subOsub2/sub-mediated inhibition of SP-B gene expression but not SP-A expression. Immunoblot analyses using specific phosphor-antibodies demonstrated that ERK1/2, p38 MAPK and STAT3 are phosphorylated by oxidative stress suggesting that Hsub2/subOsub2/sub-induced inhibition of SP-A and SP-B gene expression is associated with MAPK and JAKSTAT signaling pathway. These data, therefore, suggest that Hsub2/subOsub2 /subaffects SP-A and SP-B gene regulation by reducing TTF-1 DNA binding activity via MAPKs or STAT signaling pathways.
机译：氧化应激由包括过氧化氢（H 2 O 2 ），羟基自由基（？OH）和超氧阴离子（O 2）的活性氧（ROS）产生-），它们是细胞代谢的副产物。细胞氧化还原状态的失衡是导致各种慢性炎症疾病的潜在致病因素。在这项研究中，我们证明H 2 O 2 会降低人肺部肺上皮细胞中的表面活性剂蛋白A，B和ABCA3 mRNA水平，并增加SP-D mRNA水平。 SP的SP-A和SP-B的mRNA水平的下降是显着的，24 h后150μMH 2 O 2 的最大抑制分别为79％和87％。孵化。此外，孵育12小时后，150 µM H 2 O 2 降低ABCA3 mRNA水平，最大抑制55％。相反，孵育8小时后，150 µM H 2 O 2 导致SP-D mRNA水平增加至对照组的200％。 H 2 O 2 诱导的SP-A，SP-B，SP-D和ABCA3基因阻抑或激活被抗氧化剂N-乙酰基-预处理阻断L-半胱氨酸（NAC）和过氧化氢酶。此外，SP-A和SP-B的抑制与甲状腺转录因子-1（TTF-1）DNA结合活性降低有关，而这种降低的TTF-1结合活性可能是由于TTF-1蛋白表达水平降低所致。使用几种特定的抑制剂对可能在H 2 O 2 调控基因表达中起作用的信号转导途径的分析表明，ERK1 / 2抑制剂U0126上游激酶MEK1 / 2阻断H 2 O 2 诱导的SP-A和SP-B基因表达的抑制，而p38 MAPK抑制剂SB203580则部分抑制阻断了H 2 O 2 介导的SP-A基因表达抑制，但不抑制SP-B表达。相比之下，JAK-STAT途径的特异性抑制剂AG-490阻断了H 2 O 2 介导的SP-B基因表达的抑制，而不是SP-A表达的抑制。 。使用特异性磷抗体的免疫印迹分析表明，ERK1 / 2，p38 MAPK和STAT3被氧化应激磷酸化，表明H 2 O 2 诱导的SP-A和SP3抑制。 SP-B基因表达与MAPK和JAKSTAT信号通路相关。因此，这些数据表明，H 2 O 2 通过通过MAPKs或STAT信号通路降低TTF-1 DNA结合活性来影响SP-A和SP-B基因调控。

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