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

Publication ,  Journal Article
Li, J; Ghio, AJ; Cho, S-H; Brinckerhoff, CE; Simon, SA; Liedtke, W
Published in: Environ Health Perspect
March 2009

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.

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Published In

Environ Health Perspect

DOI

EISSN

1552-9924

Publication Date

March 2009

Volume

117

Issue

3

Start / End Page

400 / 409

Location

United States

Related Subject Headings

  • ras Proteins
  • beta-Arrestins
  • Vehicle Emissions
  • Toxicology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Respiratory Mucosa
  • Matrix Metalloproteinase 1
  • Immunohistochemistry
  • Humans
  • Gene Expression Regulation, Enzymologic
 

Citation

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Li, J., Ghio, A. J., Cho, S.-H., Brinckerhoff, C. E., Simon, S. A., & Liedtke, W. (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), 400–409. https://doi.org/10.1289/ehp.0800311
Li, Jinju, Andrew J. Ghio, Seung-Hyun Cho, Constance E. Brinckerhoff, Sidney A. Simon, and Wolfgang Liedtke. “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, no. 3 (March 2009): 400–409. https://doi.org/10.1289/ehp.0800311.
Li J, Ghio AJ, Cho S-H, Brinckerhoff CE, Simon SA, Liedtke W. 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. 2009 Mar;117(3):400–9.
Li, Jinju, et al. “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, vol. 117, no. 3, Mar. 2009, pp. 400–09. Pubmed, doi:10.1289/ehp.0800311.
Li J, Ghio AJ, Cho S-H, Brinckerhoff CE, Simon SA, Liedtke W. 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. 2009 Mar;117(3):400–409.

Published In

Environ Health Perspect

DOI

EISSN

1552-9924

Publication Date

March 2009

Volume

117

Issue

3

Start / End Page

400 / 409

Location

United States

Related Subject Headings

  • ras Proteins
  • beta-Arrestins
  • Vehicle Emissions
  • Toxicology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Respiratory Mucosa
  • Matrix Metalloproteinase 1
  • Immunohistochemistry
  • Humans
  • Gene Expression Regulation, Enzymologic