Airway smooth muscle cells are insensitive to the anti-proliferative effects of corticosteroids: The novel role of insulin growth factor binding Protein-1 in asthma

Hong Bui, Yassine Amrani, B. Deeney, Reynold A. Panettieri, Omar Tliba

Research output: Contribution to journalArticle

Abstract

Airway remodeling in asthma manifests, in part, as enhanced airway smooth muscle (ASM) mass, due to myocyte proliferation. While the anti-proliferative effects of glucocorticoid (GC) were investigated in normal ASM cells (NASMC), little is known about such effects in ASM cells derived from asthma subjects (AASMC). We posit that GC differentially modulates mitogen-induced proliferation of AASMC and NASMC. Cells were cultured, starved, then treated with Epidermal growth factor (EGF) (10 ng/ml) and Platelet-derived growth factor (PDGF) (10 ng/ml) for 24 h and/or fluticasone propionate (FP) (100 nM) added 2 h before. Cell counts and flow cytometry analyses showed that FP failed to decrease the cell number of and DNA synthesis in AASMC irrespective of mitogens used. We also examine the ability of Insulin Growth Factor Binding Protein-1 (IGFBP-1), a steroid-inducible gene that deters cell growth in other cell types, to inhibit proliferation of AASMC where FP failed. We found that FP increased IGFBP1 mRNA and protein levels. Interestingly, the addition of IGFBP1 (1 μg/ml) to FP completely inhibited the proliferation of AASMC irrespective to the mitogens used. Further investigation of different signaling molecules involved in ASM growth and GC receptor functions (Protein kinase B (PKB/AKT), Mitogen-activated protein kinases (MAPKs), Focal Adhesion Kinase (FAK)) showed that IGFBP-1 selectively decreased mitogen-induced p38 phosphorylation in AASMC. Collectively, our results show the insensitivity of AASMC to the anti-proliferative effects of GC, and demonstrate the ability of IGFBP1 to modulate AASMC growth representing, hence, a promising strategy to control ASM growth in subjects with GC insensitive asthma.

Original languageEnglish (US)
Pages (from-to)490-496
Number of pages7
JournalImmunobiology
Volume224
Issue number4
DOIs
StatePublished - Jul 2019

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Hematology

Keywords

  • Airway remodeling
  • Airway smooth muscle
  • Asthma
  • Glucocorticoid insensitivity
  • Growth
  • Proliferation

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