Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells.
Oxidative stress and cigarette smoke alter chromatin remodeling but differentially regulate NF-kappaB activation and proinflammatory cytokine release in alveolar epithelial cells.
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发表时间：
2004
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通讯作者：
F. M. Moodie;John A. Marwick;Charlotte S Anderson;P. Szulakowski;S. Biswas;M. Bauter;I. Kilty;I. Rahman
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作者：
F. M. Moodie;John A. Marwick;Charlotte S Anderson;P. Szulakowski;S. Biswas;M. Bauter;I. Kilty;I. Rahman
氧化应激由于其对促炎基因转录的影响而与肺部炎症有关。基因转录的变化取决于染色质重塑以及组蛋白乙酰转移酶 (HAT) 和组蛋白脱乙酰酶 (HDAC) 的相对活性。核组蛋白乙酰化：脱乙酰化平衡的改变可能导致特定促炎基因的转录不受控制。我们研究了过氧化氢 (H2O2) 和香烟烟雾冷凝物 (CSC) 对人肺泡上皮细胞 (A549) 中组蛋白乙酰化：脱乙酰化的影响。 H2O2 和 CSC 显着增加组蛋白 H4 蛋白的乙酰化，并与 A549 细胞中 HDAC 活性和 HDAC2 水平降低相关。此外，HDAC2 活性降低是由于醛和一氧化氮产物对蛋白质的修饰所致。用 N-乙酰基-L-半胱氨酸预处理 A549 细胞可减弱氧化剂介导的 HDAC 活性降低。用 CSC 处理 A549 细胞不会引起核因子 kappaB (NF-kappaB) 激活或白细胞介素 (IL)-8 或 IL-6 的表达和释放。然而，与对照细胞相比，H2O2、肿瘤坏死因子-α (TNF-α) 和 IL-1β 显着增加 NF-κB 激活和 IL-8 表达。有趣的是，CSC 剂量依赖性地抑制 TNF-α 和 IL-1β 介导的 NF-κB 激活和 IL-8 表达。因此，H2O2 和 CSC 增强组蛋白的乙酰化并降低组蛋白脱乙酰酶活性，但差异调节肺泡上皮细胞中促炎细胞因子的释放。
Oxidative stress is implicated in lung inflammation due to its effect on proinflammatory gene transcription. Changes in gene transcription depend on chromatin remodeling and the relative activities of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Alterations in the nuclear histone acetylation:deacetylation balance may result in uncontrolled transcription of specific proinflammatory genes. We studied the effect of hydrogen peroxide (H2O2) and cigarette smoke condensate (CSC) on histone acetylation:deacetylation in human alveolar epithelial cells (A549). H2O2 and CSC significantly increased acetylation of histone H4 proteins and were associated with decreased HDAC activity and HDAC2 levels in A549 cells. Also, the decreased HDAC2 activity was due to protein modification by aldehydes and nitric oxide products. Pretreatment of A549 cells with N-acetyl-l-cysteine attenuated the oxidant-mediated reduction in HDAC activity. Treatment of A549 cells with CSC did not cause nuclear factor-kappaB (NF-kappaB) activation or expression and release of either interleukin (IL)-8 or IL-6. However, H2O2, tumor necrosis factor-alpha (TNF-alpha), and IL-1beta significantly increased NF-kappaB activation and expression of IL-8 compared with control cells. Interestingly, CSC dose dependently inhibited TNF-alpha- and IL-1beta-mediated NF-kappaB activation and IL-8 expression. Thus, H2O2 and CSC enhance acetylation of histone proteins and decrease histone deacetylase activity but differentially regulate proinflammatory cytokine release in alveolar epithelial cells.