Nguyen M D, Simpson-Haidaris P J
Department of Microbiology and Immunology, Department of Medicine-Vascular Medicine Unit, and Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
Am J Respir Cell Mol Biol. 2000 Feb;22(2):209-17. doi: 10.1165/ajrcmb.22.2.3746.
Our recent studies demonstrating the expression of fibrinogen (FBG) by an alveolar type II cell line stimulated with proinflammatory mediators and also in the inflamed pulmonary epithelium of animals with Pneumocystis carinii pneumonia suggest that extrahepatic FBG participates in the local acute phase response (APR) to infection and subsequent wound repair. However, the mechanisms that regulate extrahepatic FBG expression are poorly understood. This study compares the regulation of hepatic and pulmonary FBG expression by mediators of the APR, interleukin (IL)-6, IL-1beta, and dexamethasone (DEX), a synthetic glucocorticoid. Northern blotting and metabolic labeling studies revealed that IL-6 with or without DEX upregulates gammaFBG messenger RNA and protein, whereas IL-1beta inhibits gammaFBG expression in human lung (A549) and liver (HepG2) epithelial cells. In contrast, the addition of DEX relieved the IL-1beta-mediated inhibition of FBG expression in lung epithelial cells only; this response is termed "DEX rescue." Studies with cycloheximide indicate that only DEX rescue required de novo protein synthesis. Nuclear run-on analysis revealed no increase in gammaFBG transcription by DEX treatment. Although DEX treatment alone increased the stability of gammaFBG transcripts in lung cells, this effect was not observed in the presence of IL-1beta. Together, these results suggest that pre-existing transcription factors mediate the effects of IL-6 with or without DEX, DEX, and IL-1beta on gammaFBG gene expression in lung and liver cells. Also, the data suggest that DEX induces new protein synthesis of an inhibitor of IL-1beta signal transduction to effectively "rescue" FBG production in lung but not liver epithelial cells. This cell type-specific stimulation of FBG production by glucocorticoids to overcome IL-1beta inhibition may promote pulmonary wound repair mechanisms.
我们最近的研究表明，肺泡II型细胞系在促炎介质刺激下以及在卡氏肺孢子虫肺炎动物的炎症肺上皮中表达纤维蛋白原（FBG），这表明肝外FBG参与了对感染的局部急性期反应（APR）以及随后的伤口修复。然而，调节肝外FBG表达的机制尚不清楚。本研究比较了APR介质白细胞介素（IL）-6、IL-1β和合成糖皮质激素地塞米松（DEX）对肝和肺FBG表达的调节作用。Northern印迹和代谢标记研究表明，无论有无DEX，IL-6均可上调γFBG信使RNA和蛋白，而IL-1β抑制人肺（A549）和肝（HepG2）上皮细胞中的γFBG表达。相反，DEX的添加仅缓解了IL-1β对肺上皮细胞中FBG表达的抑制作用；这种反应被称为“DEX挽救”。用放线菌酮进行的研究表明，只有DEX挽救需要从头合成蛋白质。核转录分析显示，DEX处理后γFBG转录没有增加。虽然单独的DEX处理增加了肺细胞中γFBG转录本的稳定性，但在存在IL-1β的情况下未观察到这种效应。总之，这些结果表明，预先存在的转录因子介导了有无DEX、DEX和IL-1β对肺和肝细胞中γFBG基因表达的影响。此外，数据表明，DEX诱导IL-1β信号转导抑制剂的新蛋白合成，以有效“挽救”肺而非肝上皮细胞中的FBG产生。糖皮质激素对FBG产生的这种细胞类型特异性刺激以克服IL-1β抑制作用，可能促进肺伤口修复机制。
