title: Endothelial cell apoptosis induced by antibodies against dengue virus nonstructural protein 1 via production of nitric oxide.
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 N(omega)-nitro-L-arginine methyl ester. Further studies demonstrated that the expression of Bcl-2 and Bcl-x(L) 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 N(omega)-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.
authors.affiliation: Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan, Republic of China.
authors.forename: Chiou-Feng
authors.initials: CF
authors.lastname: Lin
authors.forename: Huan-Yao
authors.initials: HY
authors.lastname: Lei
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Shiau
authors.forename: Hsiao-Sheng
authors.initials: HS
authors.lastname: Liu
authors.forename: Trai-Ming
authors.initials: TM
authors.lastname: Yeh
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
authors.forename: Ching-Chuan
authors.initials: CC
authors.lastname: Liu
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Chiu
authors.forename: Yee-Shin
authors.initials: YS
authors.lastname: Lin
mesh_terms: D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000276:immunology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line / Q000166:cytology / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D003716:Dengue Virus / Q000276:immunology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D017361:Viral Nonstructural Proteins / Q000276:immunology*; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
chemical_list: D000914:Antibodies, Viral; C494826:BAX protein, human; C494811:BCL2L1 protein, human; C494827:Bax protein, mouse; C494812:Bcl2l1 protein, mouse; D003574:Cytochrome c Group; C079340:NS1 protein, Dengue virus type 2; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D017361:Viral Nonstructural Proteins; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D009569:Nitric Oxide; C496319:NOS2 protein, human; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases