IL-13 and IL-1β promote lung fibroblast growth through coordinated up-regulation of PDGF-AA and PDGF-Rα
IL-13 and IL-1β promote lung fibroblast growth through coordinated up-regulation of PDGF-AA and PDGF-Rα
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DOI：
10.1096/fj.03-1492fje
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发表时间：
2004-05-01
期刊：
影响因子：
4.8
通讯作者：
Bonner, JC
中科院分区：
文献类型：
--
作者：
Ingram, JL;Rice, AB;Bonner, JC
支气管周围纤维化是哮喘气道重塑的一个显著特征，涉及成纤维细胞生长和胶原沉积。白细胞介素-13（IL-13）是一种辅助性T细胞因子，是哮喘气道重塑的关键介质，但IL-13促进成纤维细胞生长的机制尚未研究。在这项研究中，我们表明，IL-13刺激小鼠，大鼠和人肺成纤维细胞的有丝分裂，通过释放可溶性丝裂原，我们确定为PDGF-AA。IL-13诱导的人肺成纤维细胞的生长被抗PDGF-AA中和抗体减弱，并且IL-13刺激人肺成纤维细胞分泌PDGF-AA。来自具有致死性Patch突变的小鼠胚胎的成纤维细胞缺乏PDGF-Ra，对IL-13没有促有丝分裂反应。然而，Patch细胞确实表现出IL-13诱导的STAT-6磷酸化。将PDGF-Ra稳定转染到Patch细胞中恢复了对PDGF-AA和IL-13的生长反应。通过使用STAT-6缺陷小鼠的肺成纤维细胞，我们发现IL-13诱导的PDGF-AA释放是STAT-6依赖性的，但PDGF-AA诱导的生长是STAT-6独立的。最后，我们发现IL-1 β通过上调PDGF-R α增强IL-13诱导的大鼠肺成纤维细胞有丝分裂。我们的研究结果表明，IL-13与IL-1 β协同作用，分别通过协同上调PDGF-AA和PDGF-Ra刺激生长。
Peribronchiolar fibrosis is a prominent feature of airway remodeling in asthma and involves fibroblast growth and collagen deposition. Interleukin-13 (IL-13), a T-helper 2 cytokine, is a key mediator of airway remodeling in asthma, yet the mechanism through which IL-13 promotes fibroblast growth has not been investigated. In this study, we show that IL-13 stimulates the mitogenesis of mouse, rat, and human lung fibroblasts through release of a soluble mitogen that we identified as PDGF-AA. The IL-13-induced growth of human lung fibroblasts was attenuated by an anti-PDGF-AA neutralizing antibody, and IL-13 stimulated human lung fibroblasts to secrete PDGF-AA. Fibroblasts derived from mouse embryos possessing the lethal Patch mutation, which lack the PDGF-Ralpha, showed no mitogenic response to IL-13. However, Patch cells did exhibit IL-13-induced STAT-6 phosphorylation. Stable transfection of the PDGF-Ralpha into Patch cells restored the growth response to PDGF-AA and IL-13. Through the use of lung fibroblasts from STAT-6-deficient mice, we showed that IL-13-induced PDGF-AA release is STAT-6 dependent, but PDGF-AA-induced growth is STAT-6 independent. Finally, we showed that IL-1beta enhanced IL-13-induced mitogenesis of rat lung fibroblasts through up-regulation of the PDGF-Ralpha. Our findings indicate that IL-13 acts in synergy with IL-1beta to stimulate growth by coordinately up-regulating PDGF-AA and the PDGF-Ralpha, respectively.