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首页> 美国卫生研究院文献>American Journal of Respiratory Cell and Molecular Biology >Role of Bioavailable Iron in Coal Dust-Induced Activation of Activator Protein-1 and Nuclear Factor of Activated T Cells
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Role of Bioavailable Iron in Coal Dust-Induced Activation of Activator Protein-1 and Nuclear Factor of Activated T Cells

机译：生物利用铁在煤粉尘诱导的活化蛋白1和活化T细胞核因子活化中的作用

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Activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT) are two important transcription factors responsible for the regulation of cytokines, which are involved in cell proliferation and inflammation. Coal workers’ pneumoconiosis (CWP) is an occupational lung disease that may be related to chronic inflammation caused by coal dust exposure. In the present study, we demonstrate that coal from the Pennsylvania (PA) coalmine region, which has a high prevalence of CWP, can activate both AP-1 and NFAT in JB6 mouse epidermal cells. In contrast, coal from the Utah (UT) coalmine region, which has a low prevalence of CWP, has no such effects. The PA coal stimulates mitogen-activated protein kinase (MAPK) family members of extracellular signal-regulated kinases (ERKs) and p38 MAPK but not c-Jun-NH2-terminal kinases, as determined by the phosphorylation assay. The increase in AP-1 by the PA coal was completely eliminated by the pretreatment of cells with PD98059, a specific MAPK kinase inhibitor, and SB202190, a p38 kinase inhibitor, further confirming that the PA coal-induced AP-1 activation is mediated through ERKs and p38 MAPK pathways. Deferoxamine (DFO), an iron chelator, synergistically enhanced the PA coal-induced AP-1 activity, but inhibited NFAT activity. For comparison, cells were treated with ferrous sulfate and/or DFO. We have found that iron transactivated both AP-1 and NFAT, and DFO further enhanced iron-induced AP-1 activation but inhibited NFAT. These results indicate that activation of AP-1 and NFAT by the PA coal is through bioavailable iron present in the coal. These data are in agreement with our previous findings that the prevalence of CWP correlates well with levels of bioavailable iron in coals from various mining regions.
机译：活化蛋白1（AP-1）和活化T细胞核因子（NFAT）是负责调节细胞因子的两个重要转录因子，它们参与细胞增殖和炎症。煤矿工人尘肺病（CWP）是一种职业性肺部疾病，可能与接触煤尘引起的慢性炎症有关。在本研究中，我们证明了来自宾夕法尼亚州（PA）煤矿区的煤具有很高的CWP发生率，可以激活JB6小鼠表皮细胞中的AP-1和NFAT。相比之下，CWP患病率低的犹他州（UT）煤矿地区的煤炭则没有这种影响。通过磷酸化测定，PA煤刺激细胞外信号调节激酶（ERK）和p38 MAPK的促分裂原活化蛋白激酶（MAPK）家族成员，但不刺激c-Jun-NH2-末端激酶。通过用特异性MAPK激酶抑制剂PD98059和p38激酶抑制剂SB202190预处理细胞，可以完全消除PA煤对AP-1的增加，进一步证实PA煤诱导的AP-1活化是通过以下途径介导的ERK和p38 MAPK途径。铁螯合剂Deferoxamine（DFO）协同增强了PA煤诱导的AP-1活性，但抑制了NFAT活性。为了比较，将细胞用硫酸亚铁和/或DFO处理。我们已经发现，铁可同时激活AP-1和NFAT，而DFO进一步增强了铁诱导的AP-1激活，但抑制了NFAT。这些结果表明，PA煤对AP-1和NFAT的活化是通过煤中存在的可生物利用的铁实现的。这些数据与我们先前的发现一致，即CWP的流行与来自各个矿区的煤炭中生物利用铁的含量高度相关。

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