Reduced SOCS1 Expression in Lung Fibroblasts from Patients with IPF Is Not Mediated by Promoter Methylation or Mir155.

Cecilia M Prêle,Darryl A Knight,Sarra E Jamieson,Thomas Iosifidis,David R Pearce,Matthias Ernst,Philip J Thompson,Steven E Mutsaers,Bahareh Badrian,Tylah Miles,Robin J Mcanulty,Geoffrey J Laurent

doi:10.3390/biomedicines9050498

Abstract

The interleukin (IL)-6 family of cytokines and exaggerated signal transducer and activator of transcription (STAT)3 signaling is implicated in idiopathic pulmonary fibrosis (IPF) pathogenesis, but the mechanisms regulating STAT3 expression and function are unknown. Suppressor of cytokine signaling (SOCS)1 and SOCS3 block STAT3, and low SOCS1 levels have been reported in IPF fibroblasts and shown to facilitate collagen production. Fibroblasts and lung tissue from IPF patients and controls were used to examine the mechanisms underlying SOCS1 down-regulation in IPF. A significant reduction in basal SOCS1 mRNA in IPF fibroblasts was confirmed. However, there was no difference in the kinetics of activation, and methylation of SOCS1 in control and IPF lung fibroblasts was low and unaffected by 5′-aza-2′-deoxycytidine’ treatment. SOCS1 is a target of microRNA-155 and although microRNA-155 levels were increased in IPF tissue, they were reduced in IPF fibroblasts. Therefore, SOCS1 is not regulated by SOCS1 gene methylation or microRNA155 in these cells. In conclusion, we confirmed that IPF fibroblasts had lower levels of SOCS1 mRNA compared with control fibroblasts, but we were unable to determine the mechanism. Furthermore, although SOCS1 may be important in the fibrotic process, we were unable to find a significant role for SOCS1 in regulating fibroblast function.

Highlights

Exaggerated and prolonged STAT3 activation is a feature of many fibrotic disorders including liver, kidney, and lung fibrosis [4,5,6], as well as a number of cancers [32,33,34]
In idiopathic pulmonary fibrosis (IPF) lungs and those of bleomycin treated mice, STAT3 activation is localized to cells adjacent to fibrotic foci [4,5]
Based on the hypothesis that exaggerated STAT3 activity in IPF is due to altered expression and activity of Suppressor of cytokine signaling (SOCS) proteins, this study investigated mechanisms that may contribute to reduced

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, and despite an increasing number of clinical trials over the past 15 years, has limited treatment options [1,2]. IPF belongs to a group of heterogeneous lung diseases characterized by an excessive deposition of extracellular matrix (ECM) proteins within the pulmonary interstitium, leading to impaired gas exchange and loss of lung function. The pathogenesis of IPF remains poorly understood but disease progression is closely associated with regions of fibroblast accumulation and proliferation [1,3]. We have previously reported that Janus kinases (Jak)/signal transducer and activator of transcription (STAT)-mediated signaling, Biomedicines 2021, 9, 498.

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Results

Conclusion