Journal Article

Insulin-like growth factor (IGF)-II- mediated fibrosis in pathogenic lung conditions

Pilewski, Joseph M., Thomas, Justin M., Feghali-Bostwick, Carol, Hsu, Eileen, Garrett, Sara M.

2019

Overview

Type 2 insulin-like growth factor (IGF-II) levels are increased in fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and scleroderma/systemic sclerosis-associated pulmonary fibrosis (SSc). Our goal was to investigate the contribution of IGF receptors to IGF-II-mediated fibrosis in these diseases and identify other potential mechanisms key to the fibrotic process. Cognate receptor gene and protein expression were analyzed with qRT-PCR and immunoblot in primary fibroblasts derived from lung tissues of normal donors (NL) and patients with IPF or SSc. Compared to NL, steady-state receptor gene expression was decreased in SSc but not in IPF. IGF-II stimulation differentially decreased receptor mRNA and protein levels in NL, IPF, and SSc fibroblasts. Neutralizing antibody, siRNA, and receptor inhibition targeting endogenous IGF-II and its primary receptors, type 1 IGF receptor (IGF1R), IGF2R, and insulin receptor (IR) resulted in loss of the IGF-II response. IGF-II tipped the TIMP:MMP balance, promoting a fibrotic environment both intracellularly and extracellularly. Differentiation of fibroblasts into myofibroblasts by IGF-II was blocked with a TGFβ1 receptor inhibitor. IGF-II also increased TGFβ2 and TGFβ3 expression, with subsequent activation of canonical SMAD2/3 signaling. Therefore, IGF-II promoted fibrosis through IGF1R, IR, and IGF1R/IR, differentiated fibroblasts into myofibroblasts, decreased protease production and extracellular matrix degradation, and stimulated expression of two TGFβ isoforms, suggesting that IGF-II exerts pro-fibrotic effects via multiple mechanisms.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibodies / Biochemistry / Biodegradation / Biology and Life Sciences / Cell culture / Cells, Cultured / Collagen / Comparative analysis / Epigenetics / Extracellular matrix / Fibroblasts / Fibroblasts - metabolism / Fibroblasts - pathology / Fibrosis / Gene expression / Genes / Growth factors / Humans / Immunoglobulins / Insulin / Insulin-like growth factor II / Insulin-Like Growth Factor II - genetics / Insulin-Like Growth Factor II - metabolism / Insulin-like growth factor II receptors / Insulin-like growth factors / Isoforms / Lung diseases / Lungs / Matrix Metalloproteinases - genetics / Matrix Metalloproteinases - metabolism / Medicine and Health Sciences / Messenger RNA / Proteases / Proteins / Pulmonary fibrosis / Pulmonary Fibrosis - metabolism / Pulmonary Fibrosis - pathology / Receptor, IGF Type 1 - genetics / Receptor, IGF Type 1 - metabolism / Receptor, Insulin - genetics / Receptor, Insulin - metabolism / Receptors / Research and Analysis Methods / Rheumatology / RNA / Scientific equipment industry / Scleroderma / Signal Transduction / siRNA / Smad2 protein / Systemic sclerosis / Tissue Inhibitor of Metalloproteinase-1 - genetics / Tissue Inhibitor of Metalloproteinase-1 - metabolism / Tissue inhibitor of metalloproteinases / Transforming Growth Factor beta - genetics / Transforming Growth Factor beta - metabolism / Transforming growth factor-b1 / Transforming growth factors / Transplants & implants