title: Dengue virus infection mediates HMGB1 release from monocytes involving PCAF acetylase complex and induces vascular leakage in endothelial cells.
abstract: High mobility group box 1 (HMGB1) protein is released from cells as a pro-inflammatory cytokine in response to an injury or infection. During dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS), a number of pro-inflammatory cytokines are released, contributing to disease pathogenesis. In this study, the release of HMGB1 from human myelogenous leukemia cell line K562 and primary peripheral blood monocytes (PBM) cells was examined during dengue virus (DV)-infection. HMGB1 was shown to translocate from cell nuclei to the cytoplasm in both K562- and PBM-infected cells. The translocation of HMGB1 from the nucleus to the cytoplasm was shown to be mediated by the host cell p300/CBP-associated factor (PCAF) acetylase complex in K562 cells. In addition, DV capsid protein was observed to be the putative viral protein in actuating HMGB1 migration from the nucleus to cytoplasm through the involvement of PCAF acetylase. HMGB1 was released from DV-infected K562 cells into the extracellular milieu in a multiplicity of infection (M.O.I.)-independent manner and its release can be inhibited by the addition of 1-5 mM of ethyl pyruvate (EP) in a dose-dependent manner. Application of DV-infected K562 cell culture supernatants to primary endothelial cells induced vascular permeability. In contrast, supernatants from DV-infected K562 cells treated with EP or HMGB1 neutralizing antibody were observed to maintain the structural integrity of the vascular barrier.
authors.affiliation: Laboratory of Molecular RNA Virology and Antiviral Strategies, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Siew Pei
authors.initials: SP
authors.lastname: Ong
authors.forename: Ling Min
authors.initials: LM
authors.lastname: Lee
authors.forename: Yew Fai Ivan
authors.initials: YF
authors.lastname: Leong
authors.forename: Mah Lee
authors.initials: ML
authors.lastname: Ng
authors.forename: Justin Jang Hann
authors.initials: JJ
authors.lastname: Chu
mesh_terms: D000107:Acetylation; D015153:Blotting, Western; D002213:Capsid; D003715:Dengue / Q000503:physiopathology*; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000503:physiopathology; D019084:Fluorescent Antibody Technique, Indirect; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D009000:Monocytes / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D024243:HMGB1 Protein; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor