The role of Forkhead Box O 3a (FoxO3a) Transcription Factors in the Pathogenesis of Pulmonary Fibrosis

Abstract

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal interstitial pulmonary disease with no proven drug therapy and still unclear signaling mechanisms. Forkhead box O-3a (FoxO3a) transcription factor plays a major role in regulation of cell proliferation and migration. The objectives of this study are to examine how the pro-fibrotic mediators and growth factors regulate FoxO3a protein in primary human lung fibroblasts, as well as to study the role of FoxO transcription factors in the pathogenesis of IPF. We found an increase of phospho-FoxO3a (inactive FoxO3a) protein in IPF lung homogenate compared to control. Under in vitro conditions, qRT-PCR has revealed down regulation of FoxO3 in IPF fibroblasts compared to donor fibroblasts. Pro-fibrotic mediators such as transforming growth factor-ß (TGF-ß), platelet derived growth factor (PDGF)-BB and insulin-like growth factor (IGF)-1 stimulated phosphorylation of FoxO3 in human lung fibroblasts. In addition, PDGF-BB and IGF-1 treatment resulted in nuclear exclusion of FoxO3a. Wortmannin, an inhibitor of PI3K/Akt pathway, blocked PDGF-induced FoxO3a phosphorylation and nuclear exclusion of FoxO3. Paclitaxel, a FoxO3a activator, inhibited TGF-ß, PDGF-BB and IGF-1 induced-down regulation of FoxO3a expression. As well, Paclitaxel inhibited proliferation of donor and IPF fibroblast in a dose-dependent manner. Our primary data suggest that TGF-ß, PDGF-BB and IGF-1 lead to inhibition of FoxO3a transcriptional activity, thereby increasing fibroblast proliferation. FoxO activator drugs, such as Paclitaxel, inhibit fibroblast proliferation and might be used as an anti-fibrotic agent.