Brain-derived neurotrophic factor induces proliferation of human airway smooth muscle cells.

Abstract

Airway diseases such as asthma involve increased airway smooth muscle (ASM) contractility and remodelling via enhanced proliferation. Neurotrophins (NTs) such as brain-derived neurotrophic factor (BDNF), well-known in the nervous system, can regulate Ca(2+) signalling, and interact with cytokines in contributing to airway hyperreactivity. In this study, we determined whether and how BDNF regulates human ASM cell proliferation in the presence of inflammation, thus testing its potential role in airway remodelling. Cells were treated with 10 nM BDNF, 25 ng/ml tumour necrosis factor (TNF-α) or interleukin-13 (IL-13), or 10 ng/ml platelet-derived growth factor (PDGF). Proliferation was measured using CyQuant dye, with immunoblotting of cell cycle proteins predicted to change with proliferation. Forty-eight hours of BDNF enhanced ASM proliferation to ≈ 50% of that by PDGF or cytokines. Transfection with small interfering RNAs (siRNAs) targeting high-affinity tropomyosin-related kinase B receptor abolished BDNF effects on proliferation, whereas low-affinity 75 kD neurotrophin receptor (p75NTR) siRNA had no effect. Systematic pharmacologic inhibition of different components of ERK1/2 and PI3K/Akt1 pathways blunted BDNF or TNF-α-induced proliferation. BDNF also induced IκB phosphorylation and nuclear translocation of p50 and p65 NF-κB subunits, with electron mobility shift assay confirmation of NF-κB binding to consensus DNA sequence. These results demonstrate that NTs such as BDNF can enhance human ASM cell proliferation by activating proliferation-specific signalling pathways and a versatile transcription factor such as NF-κB, which are common to cytokines and growth factors involved in asthma.

• Authors: Bharathi Aravamudan, Michael Thompson, Christina Pabelick, Y S Prakash
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 16 Issue 4 Pg. 812-23 (Apr 2012) ISSN: 1582-4934 [Electronic] England
• PMID: 21651720 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

Chemical References

• Brain-Derived Neurotrophic Factor
• Interleukin-13
• Platelet-Derived Growth Factor
• Tumor Necrosis Factor-alpha

Topics

• Blotting, Western
• Brain-Derived Neurotrophic Factor (pharmacology)
• Bronchi (cytology, drug effects)
• Cell Proliferation
• Cells, Cultured
• Electrophoretic Mobility Shift Assay
• Flow Cytometry
• Humans
• Interleukin-13 (pharmacology)
• Muscle, Smooth (cytology, drug effects)
• Phosphorylation
• Platelet-Derived Growth Factor (pharmacology)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (pharmacology)