TGF-beta-mediated lung fibroblast-to-myofibroblast transition exhibits IFN-γ resistance via SHP2/SOCS3 activation

Abstract

Abstract Idiopathic pulmonary fibrosis is a lethal disease of unknown etiology. Abnormal activation of TGF-β is a common cause in developing fibrotic lesions, where Src homology-2 domain-containing phosphatase 2 (SHP2) plays a critical regulator in fibroblast activation and fibrosis. We found that a marked expression of phospho-SHP2, phospho-STAT3 and the suppressor of cytokine signaling 3 (SOCS3) were detected in bleomycin-induced rat lung fibrosis, which was highly association with pulmonary parenchymal lesions and collagen deposition. Human pulmonary fibroblasts differentiated into myofibroblasts via TGF-β1 treatment were characterized with the increased bundles of F-actin, enhanced expression of α-smooth muscle actin (α-SMA), fibronectin and collagen, which also exhibited the activation of SHP2, SOCS1/3, PIAS1, STAT3, IL-6 and IL-10. An AKT-regulated glycogen synthase kinase (GSK)-3β/SHP2 axis was induced in ROS-dependent regulation during myofibroblast differentiation. The significant retardation of interferon (IFN)-γ signaling in myofibroblasts was revealed by the decrease expression of phospho-STAT1 and IFN-γ-associated genes along with IFN-γ-inducible protein 10 (IP-10) reduction. Treatment of nintedanib (bibf1120) in myofibroblasts effectively inhibits both SHP2 and SOCS3 activation accompanying by a suppression of fibroblast-to-myofibroblast transition (FMT). Moreover, synergistic treatment of nintedanib and IFN-γ markedly ameliorated TGF-β1-mediated FMT. Accordingly, we speculate that the activation of both ROS/AKT/GSK-3β/SHP2 and IL-6/STAT3/SOCS3 axis signaling causes myofibroblasts hyposensitivity to IFN-γ whereby escaping from IFN-γ immune-surveillance during FMT.