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The dengue virus envelope protein induced PAI-1 gene expression via MEK/ERK pathways

Huey-Wen Shyu1, Yi-Ying Lin, Lien-Cheng Chen

  • 1Department of Medical Technology, Fooyin University, Kaohsiung Hsien, Taiwan. shyuhw@hotmail.com

Thrombosis and Haemostasis
|October 2, 2010
PubMed

Insights

Dengue virus EIII protein increases plasminogen activator inhibitor type I (PAI-1) production by activating MEK/ERK signaling pathways. This finding helps understand dengue hemorrhagic fever mechanisms.

Area of Science:

  • Virology
  • Molecular Biology
  • Biochemistry

Background:

  • Dengue virus (DV) infections range from mild dengue fever to severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS).
  • Elevated plasma levels of plasminogen activator inhibitor type I (PAI-1) are observed in DV-infected patients, but the underlying hemorrhagic mechanisms are unclear.
  • The role of specific DV components, like the envelope glycoprotein domain III (EIII), in modulating host responses requires further investigation.

Purpose of the Study:

  • To investigate the mechanism by which DV serotype 2 EIII protein induces PAI-1 gene expression.
  • To identify the specific signaling pathways involved in EIII-mediated PAI-1 induction.
  • To elucidate the role of the PAI-1 promoter region in this process.

Main Methods:

  • Purified recombinant DV serotype 2 EIII protein was used to treat Huh7 human hepatoma cells.
  • Gene expression and protein levels of PAI-1 were analyzed using RT-PCR and Western blot.
  • Immunofluorescence staining was employed to visualize cellular changes.
  • Reporter gene constructs with deleted PAI-1 promoter sequences were used to assess promoter activity.
  • MEK inhibitor U0126 was used to block extracellular signal-regulated kinase (ERK) signaling.

Main Results:

  • DV EIII protein significantly increased PAI-1 mRNA and protein levels in Huh7 cells in a dose-dependent manner.
  • EIII-induced PAI-1 expression was markedly suppressed by the MEK inhibitor U0126, indicating the involvement of the MEK/ERK pathway.
  • Analysis of reporter gene constructs revealed that EIII-mediated induction of PAI-1 expression occurs via the proximal promoter region.

Conclusions:

  • The MEK/ERK signaling pathway is crucial for mediating the induction of PAI-1 gene expression by DV EIII protein.
  • DV EIII protein activates PAI-1 expression through its proximal promoter region via the MEK/ERK signaling cascade.
  • Understanding this mechanism provides insights into the pathogenesis of hemorrhage in dengue virus infections.

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