Noncanonical JAK1/STAT3 interactions with TGF-β modulate myofibroblast transdifferentiation and fibrosis

Abstract

Idiopathic pulmonary fibrosis is a progressive lung disease with limited survival. The specific roles of Janus Kinases - tyrosine kinases that transduce cytokine-mediated signals - in lung fibrosis are not well defined. 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.

Centella triterpenes cream as a potential drug for the treatment of hypertrophic scar through inhibiting the phosphorylation of STAT3: A network pharmacology analysis and in vitro experiments

“…Studies have shown that TGF‐β stimulates local and bone fibroblasts to differentiate into myofibroblasts, allowing an increase in the number of myofibroblasts in HS; actin filaments in myofibroblasts contribute to wound contraction and the production of tension on the wound 45 . According to previous studies, TGF‐β can activate STAT3 or mutually regulate with STAT3 in various manners to promote fibrosis of organs and tissues 46–48 . Western blot analysis in this study showed that both AC and si‐STAT3 could significantly downregulate the TGF‐β1 protein level in HSFs, indicating a negative regulatory effect of AC on the expression and signaling of TGF‐β1 in HSFs.…”

“…or mutually regulate with STAT3 in various manners to promote fibrosis of organs and tissues. [46][47][48] Western blot analysis in this study showed that both AC and si-STAT3 could significantly downregulate the TGF-β1 protein level in HSFs, indicating a negative regulatory effect of AC on the expression and signaling of TGF-β1 in HSFs.…”

The potential mechanism of WT1‐associated protein‐induced N‐6‐methyladenosine modification of colony‐stimulating factor 2 in the progression of oral squamous cell carcinoma by JAK/STAT3 pathway regulation

“…JAK, a tyrosine kinase, facilitates STAT signaling, with JAK1 and STAT3 serving as pivotal proteins in the JAK/STAT3 pathway [25]. JAK/STAT3 signaling is known to play a crucial role in tumor cell invasion, angiogenesis, and proliferation [26].…”

Silibinin Prevents TGFβ-Induced EMT of RPE in Proliferative Vitreoretinopathy by Inhibiting Stat3 and Smad3 Phosphorylation

“…In support of this finding, several studies have demonstrated that independent of the Smad pathway, TGFβ1 can induce Stat3 phosphorylation likely through the activation of JAK1, an upstream kinase of Stat3 in other cell types. 36 , 37 More specifically, after TGFβ1 treatment, phosphorylated TβRI directly binds to and activates JAK1. Activated JAK1 can further phosphorylate Stat3.…”

“…Activated JAK1 can further phosphorylate Stat3. 37 , 38 Further evidence showed TGFβ-Jak1-Stat3 pathway is required to cooperate with Smad3 for mediating TGFβ-induced fibrotic response in hepatic stellate cells. 38 Mechanistically, phosphorylated Stat3 forms a complex with Smad3 and promotes its nuclear localization thereby enhancing fibrotic-related gene transcription.…”