Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response-1 and platelet-derived growth factor ligands in pulmonary fibroblasts
Opposing actions of Stat1 and Stat6 on IL-13-induced up-regulation of early growth response-1 and platelet-derived growth factor ligands in pulmonary fibroblasts
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DOI：
10.4049/jimmunol.177.6.4141
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发表时间：
2006-09-15
影响因子：
4.4
通讯作者：
Bonner, James C.
中科院分区：
文献类型：
--
作者：
Ingram, Jennifer L.;Antao-Menezes, Aurita;Bonner, James C.
IL-13是参与哮喘气道重塑的关键细胞因子。我们以前报道过IL-13通过血小板衍生生长因子（PDGF）-AA刺激肺成纤维细胞的有丝分裂。在这份报告中，我们表明，IL-13增加PDGF-A和PDGF-C的mRNA水平，通过一个双重的细胞内级联反应，需要共激活的Stat 6和Stat 1的影响早期生长反应（Egr）-1基因的转录调控，然后驱动PDGF的表达。在IL-13转基因小鼠的气道中观察到体内PDGF-AA和PDGF-CC蛋白水平增加。IL-13上调从三种不同背景品系小鼠分离的肺成纤维细胞中的PDGF-A和PDGF-C mRNA水平。然而，与野生型Stat 6（+/+）成纤维细胞相比，IL-13诱导的PDGF-A和PDGF-C mRNA水平在Stat 6缺陷（Stat 6（-/-））成纤维细胞中显著降低。相比之下，与Stat 1（+/+）成纤维细胞相比，IL-13诱导的PDGF-A和PDGF-C mRNA在Stat 1（-/-）成纤维细胞中增强。IL-13不上调Egr-1（-/-）成纤维细胞中PDGF-A或PDGF-C的mRNA水平。此外，IL-13并不增加Stat 6（-/-）成纤维细胞中的Egr-1 mRNA和蛋白水平，但增加Stat 1（-/-）成纤维细胞中的Egr-1 mRNA和蛋白水平。我们的研究结果支持的假设，Stat 6和Stat 1发挥刺激和抑制Egr-1和PDGF配体mRNA转录的影响，分别。这种新的机制可以帮助确定治疗哮喘慢性气道重塑和纤维化的分子靶点。
IL-13 is a key cytokine involved in airway remodeling in asthma. We previously reported that IL-13 stimulated the mitogenesis of lung fibroblasts via platelet-derived growth factor (PDGF)-AA. In this report, we show that IL-13 increases PDGF-A and PDGF-C mRNA levels through a dual intracellular cascade that requires coactivation of Stat6 and Stat1 to impact transcriptional regulation of the early growth response (Egr)-1 gene, which then drives PDGF expression. Increased levels of PDGF-AA and PDGF-CC protein were observed in vivo in the airways of IL-13 transgenic mice. IL-13 up-regulated PDGF-A and PDGF-C mRNA levels in lung fibroblasts isolated from three different background strains of mice. However, IL-13-induced PDGF-A and PDGF-C mRNA levels were significantly reduced in Stat6-deficient (Stat6(-/-)) fibroblasts as compared with wild-type Stat6(+/+) fibroblasts. In contrast, IL-13-induced PDGF-A and PDGF-C mRNAs were enhanced in Stat1(-/-) fibroblasts as compared with Stat1(+/+) fibroblasts. IL-13 did not up-regulate PDGF-A or PDGF-C mRNA levels in Egr-1(-/-) fibroblasts. Moreover, IL-13 did not increase Egr-1 mRNA and protein levels in Stat6(-/-) fibroblasts and yet enhanced Egr-1 mRNA and protein levels in Stat1(-/-) fibroblasts. Our findings support the hypothesis that Stat6 and Stat1 exert stimulatory and inhibitory effects on Egr-1 and PDGF ligand mRNA transcription, respectively. This novel mechanism could aid in identifying molecular targets for the treatment of chronic airway remodeling and fibrosis in asthma.