Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide

Chiou Feng Lin, Huan Yao Lei, Ai Li Shiau, Hsiao Sheng Liu, Trai Ming Yeh, Shun Hua Chen, Ching Chuan Liu, Shu Chen Chiu, Yee Shin Lin

Research output: Contribution to journalArticle

143 Citations (Scopus)

Abstract

The onset of vascular leakage and hemorrhagic diathesis is one of the life-threatening complications occurring in dengue patients, yet the pathogenic mechanisms are not well understood. In this study, we demonstrated that Abs against dengue virus nonstructural protein 1 (NS1) generated in mice cross-reacted with human endothelial cells and mouse vessel endothelium. After binding, mouse anti-NS1 Abs induced endothelial cell apoptosis in a caspase-dependent manner. Inducible NO synthase expression could be observed; it showed a time- and dose-dependent correlation with NO production. Endothelial cell apoptosis, characterized by exposure of phosphatidylserine on the cell surface and nuclear DNA fragmentation, was blocked by treatment with the NO synthase inhibitor Nω-nitro-L-arginine methyl ester. Further studies demonstrated that the expression of Bcl-2 and Bcl-xL decreased in both mRNA and protein levels, whereas p53 and Bax increased after anti-NS1 treatment. Cytochrome c release was also observed. All of these effects could be inhibited by Nω-nitro-L-arginine methyl ester. Taken together, anti-NS1 Abs act as autoantibodies that cross-react with noninfected endothelial cells and trigger the intracellular signaling leading to the production of NO and to apoptosis. Endothelial cell damage may cause vascular leakage that contributes to the pathogenesis of dengue disease.

Original languageEnglish
Pages (from-to)657-664
Number of pages8
JournalJournal of Immunology
Volume169
Issue number2
DOIs
Publication statusPublished - 2002 Jul 15

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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