An NF-κB-Independent and Erk1/2-Dependent Mechanism Controls CXCL8/IL-8 Responses of Airway Epithelial Cells to Cadmium
An NF-κB-Independent and Erk1/2-Dependent Mechanism Controls CXCL8/IL-8 Responses of Airway Epithelial Cells to Cadmium
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DOI：
10.1093/toxsci/kfr310
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发表时间：
2012-02-01
影响因子：
3.8
通讯作者：
Boyaka, Prosper N.
中科院分区：
文献类型：
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作者：
Cormet-Boyaka, Estelle;Jolivette, Kalyn;Boyaka, Prosper N.
肺中的气道上皮细胞是抵抗病原体和环境污染物的第一道防线。环境污染物镉的吸入与肺癌和慢性阻塞性肺病的发展有关，这些疾病的特征是慢性炎症。为了阐明气道上皮细胞在镉诱导的肺部炎症中的作用，我们研究了镉如何调节气道上皮细胞分泌白细胞介素8（IL-8）。我们发现，暴露于亚毒性剂量的镉在体外的人气道上皮细胞，促进了一个特征性的炎症细胞因子的反应组成的IL-8，但不是IL-1 β或肿瘤坏死因子-α。我们还发现，镉的鼻内递送增加小鼠IL-8同系物巨噬细胞炎性蛋白-2和keracinocyte-dervied趋化因子的肺水平，并导致Gr 1+细胞流入肺。我们确定抑制核因子-κ B（NF-κ B）通路对镉诱导的人气道上皮细胞IL-8分泌没有影响，表明IL-8的产生是通过NF-κ B非依赖性通路介导的。丝裂原活化蛋白激酶（MAPK）通常参与促炎信号传导。镉可以激活主要的MAPKs（即，p38、JNK和Erk 1/2）。然而，只有药理学抑制Erk 1/2途径或敲低Erk 1和Erk 2的表达，使用小干扰RNA抑制镉诱导的IL-8分泌。我们的研究结果确定镉作为肺上皮细胞中促炎细胞因子IL-8的有效激活剂，并首次揭示了NF-κ B非依赖性但Erk 1/2依赖性途径在镉诱导的肺部炎症中的作用。
Airway epithelial cells in the lung are the first line of defense against pathogens and environmental pollutants. Inhalation of the environmental pollutant cadmium has been linked to the development of lung cancer and chronic obstructive pulmonary disease, which are diseases characterized by chronic inflammation. To address the role of airway epithelial cells in cadmium-induced lung inflammation, we investigated how cadmium regulates secretion of interleukin 8 (IL-8) by airway epithelial cells. We show that exposure of human airway epithelial cells to subtoxic doses of cadmium in vitro promotes a characteristic inflammatory cytokine response consisting of IL-8, but not IL-1 beta or tumor necrosis factor-alpha. We also found that intranasal delivery of cadmium increases lung levels of the murine IL-8 homologs macrophage inflammatory protein-2 and keracinocyte-dervied chemokine and results in an influx of Gr1+ cells into the lung. We determined that inhibition of the nuclear factor-kappa B (NF-kappa B) pathway had no effect on cadmium-induced IL-8 secretion by human airway epithelial cells, suggesting that IL-8 production was mediated through an NF-kappa B-independent pathway. Mitogen-activated protein kinases (MAPKs) are often involved in proinflammatory signaling. Cadmium could activate the main MAPKs (i.e., p38, JNK, and Erk1/2) in human airway epithelial cells. However, only pharmacological inhibition of Erk1/2 pathway or knockdown of the expression of Erk1 and Erk2 using small interfering RNAs suppressed secretion of IL-8 induced by cadmium. Our findings identify cadmium as a potent activator of the proinflammatory cytokine IL-8 in lung epithelial cells and reveal for the first time the role of an NF-kappa B-independent but Erk1/2-dependent pathway in cadmium-induced lung inflammation.