Diesel exhaust particles activate the matrix-metalloproteinase-1 gene in human bronchial epithelia in a beta-arrestin-dependent manner via activation of RAS.
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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.
MMP-1 promoter polymorphism
Analysis of Variance
Enzyme-Linked Immunosorbent Assay
Gene Expression Regulation, Enzymologic
Matrix Metalloproteinase 1
Reverse Transcriptase Polymerase Chain Reaction
Published Version (Please cite this version)10.1289/ehp.0800311
Publication InfoBrinckerhoff, CE; Cho, SH; Ghio, Andrew J; Li, J; Liedtke, Wolfgang Bernhard; & Simon, SA (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 http://hdl.handle.net/10161/11672.
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Associate Consulting Professor of Medicine
Professor 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.
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