Non-canonical JAK1/STAT3 interactions with TGF β modulate myofibroblast trans-differentiation and fibrosis

In this study, the interactions between JAK1/STAT3 signaling and TGF-β induced fibroblast responses were investigated using both pharmacological and siRNA approaches in human normal and IPF-derived lung fibroblasts. We found that JAK1 directly interacts with the TGF-β receptor I (TβRI), and silencing JAK1 promotes myofibroblast trans-differentiation. However, the suppression of JAK1 signaling in vitro and in vivo using an inhibitor (Upadacitinib) did not alter lung fibroblast activation or fibrosis development. STAT3 was constitutively active in cultured primary lung fibroblasts: this STAT3 activation was JAK1 dependent and repressed myofibroblast trans-differentiation. Loss of phosphorylated STAT3 following transcriptional JAK1 silencing promoted myofibroblast trans-differentiation. In contrast, transcriptional silencing of unphosphorylated STAT3 suppressed TGF-β signaling, decreased SMAD3 activation, and reduced myofibroblast trans-differentiation and ECM production. Taken together, these observations support a role for JAK1/STAT3 as a direct regulator of TGF-β signaling in lung fibroblasts. Modulation of JAK1/STAT3 signaling in lung fibroblasts represents a non-canonical approach to regulate TGF-β induced fibrosis and suggests the potential for a novel approach to treat pulmonary fibrosis.PMID:36283961 | DOI:10.1152/ajplung.00428.2021

Source: American Journal of Physiology. Lung Cellular and Molecular Physiology - October 25, 2022 Category: Cytology Authors: Faping Wang Shaohua Wang Chujie Zhang Xue Tian Yongfang Zhou Weixia Xuan Eric L Matteson Fengming Luo Daniel J Tschumperlin Robert Vassallo Source Type: research