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

English version

Autoři: Sara M. Garrett ^aff001; Eileen Hsu ^aff002; Justin M. Thomas ^aff003; Joseph M. Pilewski ^aff004; Carol Feghali-Bostwick ^aff001
Působiště autorů: Division of Rheumatology, Department of Medicine, Medical University of South Carolina (MUSC), Charleston, South Carolina, United States of America ^aff001; Mid Atlantic Permanente Medical Group, Mclean, Virginia, United States of America ^aff002; Eisenhower Medical Center, Rancho Mirage, California, United States of America ^aff003; Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America ^aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0225422

Souhrn

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.

Klíčová slova:

Collagens – Fibroblasts – Fibrosis – Gene expression – Protein expression – Pulmonary fibrosis – Small interfering RNAs – TGF-beta signaling cascade

Zdroje

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

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