Uranium induces TNFα secretion and MAPK activation in a rat alveolar macrophage cell line
Uranium induces TNFα secretion and MAPK activation in a rat alveolar macrophage cell line
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DOI：
10.1016/j.taap.2003.08.016
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发表时间：
2004-01-01
影响因子：
3.8
通讯作者：
Raoul, H
中科院分区：
文献类型：
--
作者：
Gazin, V;Kerdine, S;Raoul, H
铀是一种有毒重金属，主要存在于核工业中，但也用于制造军火。使用动物模型进行的吸入研究表明，长期接触铀可导致肺部肿瘤和纤维化的发生。由于已证明此类作用通常与炎症相关，因此使用 NR8383 细胞系在体外评估了铀对巨噬细胞 TNFα、IL-1β 和 IL-10 合成的影响。我们的结果表明，铀诱导了显着的 TNFα 分泌，但其他金属（例如钆）则不诱导 TNFα 分泌。然而，IL-1β和IL-10的分泌不受铀处理的影响。从 50 μM 铀开始可检测到 TNFα 分泌，并在暴露 24 It 后达到最大。通过评估蛋白激酶的激活来确定铀诱导的 TNFα 产生的机制。我们的结果表明，铀处理诱导 c-Jun N 末端激酶 (JNK) 和 p38 丝裂原激活蛋白激酶 (p38 MAPK) 激活。药物抑制剂的使用表明 p38 MAPK 和蛋白激酶 C (PKC) 均参与铀诱导的 TNFα 分泌的信号转导。 TNFα 分泌的调节至少通过 TNFα mRNA 的稳定而涉及 TNFα mRNA 的积累，但 p38 MAPK 似乎不参与这种稳定。然而，这一观察结果并不排除 TNFα 的调节。转录水平的合成，仍有待证明。综上所述，这些结果表明铀可以诱导巨噬细胞分泌TNFα，从而有助于更好地了解铀对肺部的病理作用。 (C) 2003 Elsevier Inc. 保留所有权利。
Uranium is a toxic heavy metal found mainly in the nuclear industry, but it is also used in the manufacturing of military munitions. Inhalation studies using animal models have demonstrated that long-term exposure to uranium can lead to the development of neoplasia and fibrosis at the pulmonary level. Because it has been demonstrated that such effects are often associated with inflammation, the effect of uranium on TNFalpha IL-1beta, and IL-10 synthesis by macrophages was assessed in vitro using the NR8383 cell line. Our results show that a significant TNFalpha secretion was induced by uranium but not by other metals such as gadolinium. However, IL-1beta and IL-10 secretions were unaffected by uranium treatment. TNFalpha secretion was detectable since 50 muM of uranium and was maximal after 24 It of exposure. Determination of the mechanisms of uranium-induced TNFalpha production was assessed through the evaluation of protein kinases activation. Our results showed that uranium treatment induced c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) activation. The use of pharmacological inhibitors suggested that both p38 MAPK and protein kinase C (PKC) participate in the signal transduction of uranium-induced TNFalpha secretion. The regulation of TNFalpha secretion involves TNFalpha mRNA accumulation at least through the stabilization of TNFalpha mRNA, but p38 MAPK did not appear to be involved in this stabilization. However, this observation does not exclude regulation of TNFalpha. synthesis at the transcriptional level, which remains to be demonstrated. Taking together, these results suggest that uranium can induce TNFalpha secretion by macrophages, thus contributing to a better understanding of the pathological effect of uranium on the lung. (C) 2003 Elsevier Inc. All rights reserved.