Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS.

Li, Jinju

Ghio, Andrew J

Cho, Seung-Hyun

Brinckerhoff, Constance E

Simon, Sidney A

Liedtke, Wolfgang

United States

2016-03-01T15:05:14Z

2009-03

BACKGROUND: Diesel exhaust particles (DEPs) are globally relevant air pollutants that exert a detrimental human health impact. However, mechanisms of damage by DEP exposure to human respiratory health and human susceptibility factors are only partially known. Matrix metalloproteinase-1 (MMP-1) has been implied as an (etio)pathogenic factor in human lung and airway diseases such as emphysema, chronic obstructive pulmonary disease, chronic asthma, tuberculosis, and bronchial carcinoma and has been reported to be regulated by DEPs. OBJECTIVE: We elucidated the molecular mechanisms of DEPs' up-regulation of MMP-1. METHODS/RESULTS: Using permanent and primary human bronchial epithelial (HBE) cells at air-liquid interface, we show that DEPs activate the human MMP-1 gene via RAS and subsequent activation of RAF-MEK-ERK1/2 mitogen-activated protein kinase signaling, which can be scaffolded by beta-arrestins. Short interfering RNA mediated beta-arrestin1/2 knockout eliminated formation, subsequent nuclear trafficking of phosphorylated ERK1/2, and resulting MMP-1 transcriptional activation. Transcriptional regulation of the human MMP-1 promoter was strongly influenced by the presence of the -1607GG polymorphism, present in 60-80% of humans, which led to striking up-regulation of MMP-1 transcriptional activation. CONCLUSION: Our results confirm up-regulation of MMP-1 in response to DEPs in HBE and provide new mechanistic insight into how these epithelia, the first line of protection against environmental insults, up-regulate MMP-1 in response to DEP inhalation. These mechanisms include a role for the human -1607GG polymorphism as a susceptibility factor for an accentuated response, which critically depends on the ability of beta-arrestin1/2 to generate scaffolding and nuclear trafficking of phosphorylated ERK1/2.

http://www.ncbi.nlm.nih.gov/pubmed/19337515

1552-9924

https://hdl.handle.net/10161/11672

eng

Environmental Health Perspectives

Environ Health Perspect

10.1289/ehp.0800311

MAP kinase

MMP-1

MMP-1 promoter polymorphism

bronchial epithelia

diesel particles

urban smog

β-arrestin

Analysis of Variance

Arrestins

Blotting, Western

Bronchi

Cell Line

DNA Primers

Enzyme-Linked Immunosorbent Assay

Gene Expression Regulation, Enzymologic

Humans

Immunohistochemistry

Matrix Metalloproteinase 1

Respiratory Mucosa

Reverse Transcriptase Polymerase Chain Reaction

Vehicle Emissions

beta-Arrestins

ras Proteins

Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS.

Journal article

Liedtke, Wolfgang|0000-0003-4166-5394

http://www.ncbi.nlm.nih.gov/pubmed/19337515

400

409

3

Anesthesiology

Basic Science Departments

Clinical Science Departments

Duke

Duke Institute for Brain Sciences

Institutes and Provost's Academic Units

Neurobiology

Neurology

Neurology, Headache and Pain

School of Medicine

University Institutes and Centers

Published

117