IPF pathogenesis is dependent upon TGFβ induction of IGF-1

Danielle M. Hernandez, Jeong Han Kang, Malay Choudhury, Mahefatiana Andrianifahanana, Xueqian Yin, Andrew H. Limper, Edward B. Leof

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

Pathogenic fibrotic diseases, including idiopathic pulmonary fibrosis (IPF), have some of the worst prognoses and affect millions of people worldwide. With unclear etiology and minimally effective therapies, two-thirds of IPF patients die within 2-5 years from this progressive interstitial lung disease. Transforming Growth Factor Beta (TGFβ) and insulin-like growth factor-1 (IGF-1) are known to promote fibrosis; however, myofibroblast specific upregulation of IGF-1 in the initiation and progression of TGFβ-induced fibrogenesis and IPF have remained unexplored. To address this, the current study (1) documents the upregulation of IGF-1 via TGFβ in myofibroblasts and fibrotic lung tissue, as well as its correlation with decreased pulmonary function in advanced IPF; (2) identifies IGF-1's C1 promoter as mediating the increase in IGF-1 transcription by TGFβ in pulmonary fibroblasts; (3) determines that SMAD2 and mTOR signaling are required for TGFβ-dependent Igf-1 expression in myofibroblasts; (4) demonstrates IGF-1R activation is essential to support TGFβ-driven profibrotic myofibroblast functions and excessive wound healing; and (5) establishes the effectiveness of slowing the progression of murine lung fibrosis with the IGF-1R inhibitor OSI-906. These findings expand our knowledge of IGF-1's role as a novel fibrotic-switch, bringing us one step closer to understanding the complex biological mechanisms responsible for fibrotic diseases and developing effective therapies.

Original languageEnglish (US)
Pages (from-to)5363-5388
Number of pages26
JournalFASEB Journal
Volume34
Issue number4
DOIs
StatePublished - Apr 1 2020

Keywords

  • fibroblast
  • promoter
  • signaling
  • transcription

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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    Hernandez, D. M., Kang, J. H., Choudhury, M., Andrianifahanana, M., Yin, X., Limper, A. H., & Leof, E. B. (2020). IPF pathogenesis is dependent upon TGFβ induction of IGF-1. FASEB Journal, 34(4), 5363-5388. https://doi.org/10.1096/fj.201901719RR