Antibodies against dengue virus nonstructural protein-1 induce heme oxygenase-1 via a redox-dependent pathway in human endothelial cells

Free Radic Biol Med. 2013 Jan:54:85-92. doi: 10.1016/j.freeradbiomed.2012.10.551. Epub 2012 Oct 26.


Heme oxygenase (HO)-1, the inducible isoform of the first and rate-limiting enzyme of heme degradation, affords anti-inflammatory protection via its cell-type-specific effects in endothelial cells (ECs). In dengue hemorrhagic fever (DHF), which is the life-threatening form of dengue virus (DV) infection, endothelial interactions of cross-reactive antibodies against the DV nonstructural glycoprotein-1 (NS1) are associated with endothelial dysfunction. In this study, we investigated whether anti-NS1 antibodies might regulate HO-1 gene expression in human ECs. Serum from DHF patients with high anti-NS1 titers and a monoclonal anti-NS1 antibody upregulated HO-1 gene expression in human umbilical vein ECs, which was blocked by purified NS1 antigen. Immunoprecipitation studies showed that anti-NS1 antibodies specifically bound to the oxidoreductase protein disulfide isomerase (PDI) on ECs. Moreover, anti-NS1-mediated HO-1 induction was reduced by inhibition of PDI enzyme activity. Reactive oxygen species, which were generated by NADPH oxidase and in turn activated the phosphatidylinositol 3-kinase (PI3K)/Akt cascade, were involved in this upregulation of HO-1 gene expression. Finally, apoptosis of ECs caused by anti-NS1 antibodies was increased by pharmacological inhibition of HO-1 enzyme activity. In conclusion, HO-1 gene expression is upregulated by anti-NS1 antibodies via activation of a redox-dependent PDI/PI3K/Akt-mediated pathway in human ECs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Viral / blood
  • Antibodies, Viral / pharmacology
  • Apoptosis / drug effects
  • Cells, Cultured
  • Dengue / immunology*
  • Dengue Virus / immunology*
  • Gene Expression Regulation
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / physiology*
  • Human Umbilical Vein Endothelial Cells / virology
  • Humans
  • Oxidation-Reduction
  • Phosphatidylinositol 3-Kinases / metabolism
  • Protein Disulfide Reductase (Glutathione) / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects
  • Viral Nonstructural Proteins / immunology
  • Viral Nonstructural Proteins / metabolism*


  • Antibodies, Viral
  • NS1 protein, Dengue virus type 2
  • Reactive Oxygen Species
  • Viral Nonstructural Proteins
  • Heme Oxygenase-1
  • Protein Disulfide Reductase (Glutathione)
  • Phosphatidylinositol 3-Kinases