Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS.
Abstract
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.
Type
Journal articleSubject
MAP kinaseMMP-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
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https://hdl.handle.net/10161/11672Published Version (Please cite this version)
10.1289/ehp.0800311Publication Info
Li, Jinju; Ghio, Andrew J; Cho, Seung-Hyun; Brinckerhoff, Constance E; Simon, Sidney
A; & Liedtke, Wolfgang (2009). Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial
epithelia in a beta-arrestin-dependent manner via activation of RAS. Environ Health Perspect, 117(3). pp. 400-409. 10.1289/ehp.0800311. Retrieved from https://hdl.handle.net/10161/11672.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Wolfgang Bernhard Liedtke
Adjunct Professor in the Department of Neurology
Research Interests in the Liedtke-Lab:
Pain/ nociception
Sensory transduction and -transmission
TRP ion channels
Water and salt equilibrium regulated by the central nervous system
Visit the lab's website, download papers and read Dr. Liedtke's CV here.
Sidney Arthur Simon
Professor Emeritus of Neurobiology
Dr. Simon's laboratory studies the interaction of chemical stimuli with cultured and
intact trigeminal ganglion neurons and taste receptor cells both in culture, in anesthetized
and in awake behaving animals. We investigate how chemicals that are either bitter
and/or irritating ( e.g., nicotine, capsaicin, colloidal particles) interact with
particular types of receptors (e.g. nicotinic acetylcholine receptors or vanilloid
receptors) to produce a bitter, irritating or painful sensation. We a
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