IL‐13 and IL‐1β promote lung fibroblast growth through coordinated up‐regulation of PDGF‐AA and PDGF‐Rα

ABSTRACT 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‐Rα, showed no mitogenic response to IL‐13. However, Patch cells did exhibit IL‐13‐induced STAT‐6 phosphorylation. Stable transfection of the PDGF‐Rα 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‐1β enhanced IL‐13‐induced mitogenesis of rat lung fibroblasts through up‐regulation of the PDGF‐Rα. Our findings indicate that IL‐13 acts in synergy with IL‐1β to stimulate growth by coordinately up‐regulating PDGF‐AA and the PDGF‐Rα, respectively.