title: Antibodies against dengue virus nonstructural protein-1 induce heme oxygenase-1 via a redox-dependent pathway in human endothelial cells.
abstract: 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.
authors.affiliation: Institute for Transfusion Medicine, Hannover Medical School, 30625 Hannover, Germany. Immenschuh.Stephan@mh-hannover.de
authors.forename: Stephan
authors.initials: S
authors.lastname: Immenschuh
authors.forename: Puji
authors.initials: P
authors.lastname: Rahayu
authors.forename: Behnat
authors.initials: B
authors.lastname: Bayat
authors.forename: Hendry
authors.initials: H
authors.lastname: Saragih
authors.forename: Andhika
authors.initials: A
authors.lastname: Rachman
authors.forename: Sentot
authors.initials: S
authors.lastname: Santoso
mesh_terms: D000914:Antibodies, Viral / Q000097:blood / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D003715:Dengue / Q000276:immunology*; D003716:Dengue Virus / Q000276:immunology*; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology* / Q000821:virology; D006801:Humans; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011490:Protein Disulfide Reductase (Glutathione) / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000276:immunology / Q000378:metabolism*
chemical_list: D000914:Antibodies, Viral; C079340:NS1 protein, Dengue virus type 2; D017382:Reactive Oxygen Species; D017361:Viral Nonstructural Proteins; D051547:Heme Oxygenase-1; D011490:Protein Disulfide Reductase (Glutathione); D019869:Phosphatidylinositol 3-Kinases