TNF-α inhibits SP-A gene expression in lung epithelial cells via p38 MAPK
TNF-α inhibits SP-A gene expression in lung epithelial cells via p38 MAPK
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DOI：
10.1152/ajplung.00470.2001
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发表时间：
2002-08-01
影响因子：
4.9
通讯作者：
Snyder, JM
中科院分区：
文献类型：
--
作者：
Miakotina, OL;Snyder, JM
肺表面活性物质蛋白A(SP-A)是主要的肺表面活性物质相关蛋白，介导局部抗病原体和调节肺泡炎症。肿瘤坏死因子-α是一种促炎症细胞因子，可抑制肺上皮细胞SP-A基因的表达。磷脂酰肌醇3-激酶途径的抑制剂Wortmannin、LY-294002和雷帕霉素不能阻断肿瘤坏死因子-α对SP-amRNA水平的抑制作用。P44/42丝裂原活化蛋白激酶(MAPK)通路的抑制剂PD-98059也无效。P38MAPK抑制剂PD-169316和SB-203580可阻断肿瘤坏死因子α对SP-A基因表达的抑制作用。在15min内，肿瘤坏死因子-α使p38MAPK的磷酸化水平升高。P38MAPK的激活剂樟柳霉素以剂量依赖的方式增加p38MAPK的磷酸化，降低SP-A的mRNA水平。最后，肿瘤坏死因子-α增加了转录因子ATF-2的磷酸化，ATF-2是p38MAPK底物。结论：肿瘤坏死因子-α通过p38MAPK信号转导途径下调肺上皮细胞SP-A基因的表达。
Surfactant protein A (SP-A), the major lung surfactant-associated protein, mediates local defense against pathogens and modulates inflammation in the alveolus. Tumor necrosis factor (TNF)-alpha, a proinflammatory cytokine, inhibits SP-A gene expression in lung epithelial cells. Inhibitors of the phosphatidylinositol 3-kinase pathway, i.e., wortmannin, LY-294002, and rapamycin, did not block the inhibitory effects of TNF-alpha on SP-A mRNA levels. An inhibitor of the p44/42 mitogen-activated protein kinase (MAPK) pathway, PD-98059, was also ineffective. PD-169316 and SB-203580, inhibitors of p38 MAPK, blocked the TNF-alpha-mediated inhibition of SP-A mRNA levels. TNF-alpha increased the phosphorylation of p38 MAPK within 15 min. Anisomycin, an activator of p38 MAPK, increased p38 MAPK phosphorylation and decreased SP-A mRNA levels in a dose-dependent manner. Finally, TNF-alpha increased the phosphorylation of ATF-2, a transcription factor that is a p38 MAPK substrate. We conclude that TNF-alpha downregulates SP-A gene expression in lung epithelial cells via the p38 MAPK signal transduction pathway.