Inflammation accelerates copper‐mediated cytotoxicity through induction of six‐transmembrane epithelial antigens of prostate 4 expression,Immunology and Cell Biology

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Inflammation accelerates copper‐mediated cytotoxicity through induction of six‐transmembrane epithelial antigens of prostate 4 expression
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2020-11-12 , DOI: 10.1111/imcb.12427
Cen Jiang ₁ , Beiying Wu ₁ , Minghui Xue ₁ , Jiafei Lin ₁ , Zhenli Hu ₂ , Xiaomeng Nie ₂ , Gang Cai ₁

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Copper is an essential trace metal, but imbalance in copper homeostasis can induce oxidative damage. Inflammation is a fundamental element of various pulmonary diseases. Although a positive relationship between copper and chronic pulmonary diseases has been reported, the underlying reasons are still not clear. The copper level in the sputum of patients with various pulmonary diseases was measured. An inflammatory model was established to evaluate the impact of inflammation on copper uptake in the lung. We found that the level of sputum copper was increased in patients with various pulmonary diseases, especially chronic obstructive pulmonary disease and asthma. Then, we confirmed that mice with pulmonary inflammation were susceptible to copper‐mediated oxidative damage because of copper overload in lung tissue. Further investigation demonstrated that interleukin (IL)‐17 and tumor necrosis factor (TNF)‐α exerted synergistic effects in airway epithelial cells by upregulating the expression of six‐transmembrane epithelial antigens of prostate 4 (STEAP4), a metalloreductase that reduces extracellular copper ions from the cupric state to the cuprous state and facilitates copper uptake. Inhibition of STEAP4 decreased the copper uptake of cells and inhibited copper‐mediated oxidative damage. Moreover, we demonstrated that the upregulation of STEAP4 by IL‐17 and TNF‐α was largely dependent on TNF receptor‐associated factor 4 (TRAF4). Traf4^−/− mice were resistant to copper‐mediated oxidative damage. Our data suggest a novel IL‐17/TNF‐α–TRAF4–STEAP4 axis that regulates copper homeostasis.

中文翻译：

炎症通过诱导前列腺 4 表达的六跨膜上皮抗原加速铜介导的细胞毒性

铜是一种必不可少的微量金属，但铜稳态失衡会导致氧化损伤。炎症是各种肺部疾病的基本要素。尽管已报道铜与慢性肺病之间存在正相关关系，但其根本原因仍不清楚。测量了各种肺部疾病患者痰液中的铜含量。建立炎症模型以评估炎症对肺中铜摄取的影响。我们发现各种肺部疾病，尤其是慢性阻塞性肺疾病和哮喘患者的痰铜水平升高。然后，我们证实肺部炎症小鼠由于肺组织中的铜过载而容易受到铜介导的氧化损伤。进一步的研究表明，白细胞介素 (IL)-17 和肿瘤坏死因子 (TNF)-α 通过上调前列腺六跨膜上皮抗原 4 (STEAP4) 的表达，在气道上皮细胞中发挥协同作用，STEAP4 是一种减少细胞外铜离子的金属还原酶从铜态到亚铜态并促进铜的吸收。抑制 STEAP4 会降低细胞对铜的摄取并抑制铜介导的氧化损伤。此外，我们证明 IL-17 和 TNF-α 对 STEAP4 的上调很大程度上依赖于 TNF 受体相关因子 4（TRAF4）。一种金属还原酶，可将细胞外铜离子从铜态还原为亚铜态并促进铜吸收。抑制 STEAP4 会降低细胞对铜的摄取并抑制铜介导的氧化损伤。此外，我们证明 IL-17 和 TNF-α 对 STEAP4 的上调很大程度上依赖于 TNF 受体相关因子 4（TRAF4）。一种金属还原酶，可将细胞外铜离子从铜态还原为亚铜态并促进铜吸收。抑制 STEAP4 会降低细胞对铜的摄取并抑制铜介导的氧化损伤。此外，我们证明 IL-17 和 TNF-α 对 STEAP4 的上调很大程度上依赖于 TNF 受体相关因子 4（TRAF4）。Traf4 ^-/-小鼠对铜介导的氧化损伤具有抵抗力。我们的数据表明一个新的 IL-17/TNF-α-TRAF4-STEAP4 轴可以调节铜稳态。

更新日期：2020-11-12

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