Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation

Chia-Ling Chen, Chiou Feng Lin, Shu-Wen Wan, Li-Shiung Wei, Mei-Chun Chen, Trai-Ming Yeh, Hsiao-Sheng Liu, Robert Anderson, Yee-Shin Lin

Research output: Contribution to journalArticle

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Abstract

Immunopathogenetic mechanisms of dengue virus (DENV) infection are involved in hemorrhagic syndrome resulting from thrombocytopenia, coagulopathy, and vasculopathy. We have proposed a mechanism of molecular mimicry in which Abs against DENV nonstructural protein 1 (NS1) cross-react with human endothelial cells and cause NF-κB-regulated immune activation and NO-mediated apoptosis. However, the signaling pathway leading to NF-κB activation after the binding of anti-DENV NS1 Abs to endothelial cells is unresolved. In this study, we found that anti-DENV NS1 Abs caused the formation of lipid raftlike structures, and that disrupting lipid raft formation by methyl-β-cyclodextrin decreased NO production and apoptosis. Treatment with anti-DENV NS1 Abs elevated ceramide generation in lipid rafts. Pharmacological inhibition of acid sphingomyelinase (aSMase) decreased anti-DENV NS1 Ab-mediated ceramide and NO production, as well as apoptosis. Exogenous ceramide treatment induced biogenesis of inducible NO synthase (iNOS)/NO and apoptosis through an NF-κB-regulated manner. Furthermore, activation of glycogen synthase kinase-3β (GSK-3β) was required for ceramide-induced NF-κB activation and iNOS expression. Notably, anti-DENV NS1 Abs caused GSK-3β-mediated NF-κB activation and iNOS expression, which were regulated by aSMase. Moreover, pharmacological inhibition of GSK-3β reduced hepatic endothelial cell apoptosis in mice passively administered anti-DENV NS1 Abs. These results suggest that anti-DENV NS1 Abs bind to the endothelial cell membrane and cause NO production and apoptosis via a mechanism involving the aSMase/ceramide/GSK-3β/NF-κB/iNOS/NO signaling pathway.

Original languageEnglish
Pages (from-to)1744-1752
Number of pages9
JournalJournal of Immunology
Volume191
Issue number4
DOIs
Publication statusPublished - Aug 15 2013

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Glycogen Synthase Kinase 3
Dengue Virus
Ceramides
Endothelial Cells
Apoptosis
Antibodies
Sphingomyelin Phosphodiesterase
Nitric Oxide Synthase
Proteins
Lipids
Acids
Pharmacology
Molecular Mimicry
Cyclodextrins
Virus Diseases
Thrombocytopenia
Hepatocytes
Cell Membrane

ASJC Scopus subject areas

  • Immunology

Cite this

Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation. / Chen, Chia-Ling; Lin, Chiou Feng; Wan, Shu-Wen; Wei, Li-Shiung; Chen, Mei-Chun; Yeh, Trai-Ming; Liu, Hsiao-Sheng; Anderson, Robert; Lin, Yee-Shin.

In: Journal of Immunology, Vol. 191, No. 4, 15.08.2013, p. 1744-1752.

Research output: Contribution to journalArticle

Chen, Chia-Ling ; Lin, Chiou Feng ; Wan, Shu-Wen ; Wei, Li-Shiung ; Chen, Mei-Chun ; Yeh, Trai-Ming ; Liu, Hsiao-Sheng ; Anderson, Robert ; Lin, Yee-Shin. / Anti-dengue virus nonstructural protein 1 antibodies cause NO-mediated endothelial cell apoptosis via ceramide-regulated glycogen synthase kinase-3β and NF-κB activation. In: Journal of Immunology. 2013 ; Vol. 191, No. 4. pp. 1744-1752.
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AU - Wei, Li-Shiung

AU - Chen, Mei-Chun

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AU - Anderson, Robert

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