Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages.
Role of iron in NF-kappa B activation and cytokine gene expression by rat hepatic macrophages.
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DOI：
10.1152/ajpgi.1997.272.6.g1355
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发表时间：
1997-06
期刊：
影响因子：
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通讯作者：
Min Lin;R. Rippe;O. Niemelä;G. Brittenham;H. Tsukamoto
中科院分区：
文献类型：
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作者：
Min Lin;R. Rippe;O. Niemelä;G. Brittenham;H. Tsukamoto
氧化还原敏感核因子 NF-kappa B 可诱导巨噬细胞中肿瘤坏死因子-α (TNF-α) 和白细胞介素 6 (IL-6) 的转录。本研究调查了铁在大鼠肝巨噬细胞 (HM) NF-κ B 激活以及 TNF-α 和 IL-6 表达中的作用。作为体内模型，通过结扎胆总管（BDL）在大鼠中诱导胆汁淤积性肝损伤。 BDL 后的前 2 周内，肝脏硫代巴比妥酸反应物质 (TBARS) 水平升高，同时门静脉周围区域出现蛋白质-丙二醛加合物。 3周后这种增加减少了。 BDL 大鼠 HM 中的 TNF-α 和 IL-6 mRNA 水平在第 1 周和第 2 周时增加，并在第 3 周时减弱。 HM 核提取物的凝胶迁移率变化测定证明了 NF-κ B 结合活性增强的类似时间模式。用亲脂性铁螯合剂 1,2-二甲基-3-羟基吡啶-4-酮 (L-1) 治疗 BDL 动物，可抑制肝脏 TBARS 的增加 64%，血浆丙氨酸氨基转移酶的增加抑制 45%，以及 HM TNF-α 和 IL-6 mRNA 的增加> 84%。与此同时，HM NF-κ B 结合活性降低至接近假手术大鼠中观察到的水平。用 L-1 处理培养的 HM 还可在 mRNA 和蛋白质水平上阻断脂多糖刺激的 NF-κ B 激活以及 TNF-α 和 IL-6 表达。这些结果表明，在胆汁淤积性肝损伤或体外脂多糖刺激下，铁螯合剂可有效阻断 NF-κ B 激活并协调 HM 上调 TNF-α 和 IL-6 基因。这些发现支持铁在体外和体内 HM 激活 NF-κ B 和细胞因子基因表达中的关键作用。
A redox-sensitive nuclear factor, NF-kappa B, induces transcription of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in macrophages. The present study has investigated the role of iron in NF-kappa B activation and TNF-alpha and IL-6 expression by rat hepatic macrophages (HM). As an in vivo model, cholestatic liver injury was induced in rats by ligation of the common bile duct (BDL). During the first 2 wk after BDL, there was an increase in the hepatic level of thiobarbituric acid-reactive substances (TBARS) that was accompanied by the appearance of protein-malondialdehyde adducts in the periportal region. This increase was reduced after 3 wk. TNF-alpha and IL-6 mRNA levels in HM from the BDL rats were increased at 1 and 2 wk and attenuated at 3 wk. Gel mobility shift assay of HM nuclear extracts demonstrated the similar temporal pattern of enhanced NF-kappa B binding activity. Treatment of the BDL animals with 1,2-dimethyl-3-hydroxypyrid-4-one (L-1), a lipophilic iron chelator, suppressed the increases in hepatic TBARS by 64%, plasma alanine aminotransferase by 45%, and HM TNF-alpha and IL-6 mRNA by > 84%. Concomitantly, the HM NF-kappa B binding activity was reduced close to the level observed in sham-operated rats. Treatment of cultured HM with L-1 also blocked lipopolysaccharide-stimulated NF-kappa B activation and TNF-alpha and IL-6 expression at mRNA and protein levels. These results demonstrate that the iron chelator effectively blocks NF-kappa B activation and coordinate TNF-alpha and IL-6 gene upregulation by HM in cholestatic liver injury or under in vitro lipopolysaccharide stimulation. These findings support a pivotal role for iron in activation of NF-kappa B and cytokine gene expression by HM in vitro and in vivo.