title: Protective effect of the long pentraxin PTX3 against histone-mediated endothelial cell cytotoxicity in sepsis.
abstract: Pentraxin 3 (PTX3), a member of the long pentraxin subfamily within the family of pentraxins, is a soluble pattern recognition molecule that functions in the innate immune system. Innate immunity affords the infected host protection against sepsis, a potentially life-threatening inflammatory response to infection. Extracellular histones are considered to be the main cause of septic death because of their cytotoxic effect on endothelial cells, which makes them a potential therapeutic target. We found that PTX3 interacted with histones to form coaggregates, which depended on polyvalent interactions and disorder in the secondary structure of PTX3. PTX3 exerted a protective effect, both in vitro and in vivo, against histone-mediated cytotoxicity toward endothelial cells. Additionally, the intraperitoneal administration of PTX3 reduced mortality in mouse models of sepsis. The amino-terminal domain of PTX3, which was required for coaggregation with histones, was sufficient to protect against cytotoxicity. Our results suggest that the host-protective effects of PTX3 in sepsis are a result of its coaggregation with histones rather than its ability to mediate pattern recognition. This long pentraxin-specific effect provides a potential basis for the treatment of sepsis directed at protecting cells from the toxic effects of extracellular histones.
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Daigo
authors.affiliation: Laboratory of Medical Proteomics, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakakido
authors.affiliation: Division of Cellular and Molecular Pathology, Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. Department of Pathology, Niigata University Medical and Dental Hospital, Niigata 951-8520, Japan.
authors.forename: Riuko
authors.initials: R
authors.lastname: Ohashi
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Fukuda
authors.affiliation: Division of Cellular and Molecular Pathology, Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsubara
authors.affiliation: Laboratory for Vascular Biology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Minami
authors.affiliation: Department of Emergency and Critical Care Medicine, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan.
authors.forename: Naotaka
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Department of Cardiology, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Inoue
authors.affiliation: Division of Cellular and Molecular Pathology, Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan. Niigata College of Medical Technology, Niigata 950-2076, Japan. Perseus Proteomics Inc., Tokyo 153-0041, Japan.
authors.forename: Shuying
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Division of Cellular and Molecular Pathology, Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Naito
authors.affiliation: Laboratory of Medical Proteomics, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
authors.forename: Kouhei
authors.initials: K
authors.lastname: Tsumoto
authors.affiliation: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan. hamakubo@qbm.rcast.u-tokyo.ac.jp.
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006657:Histones / Q000378:metabolism*; D007113:Immunity, Innate / Q000276:immunology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017433:Protein Structure, Secondary / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D018805:Sepsis / Q000276:immunology*; D016019:Survival Analysis; D000099153:Pentraxins
chemical_list: D002097:C-Reactive Protein; D006657:Histones; D009419:Nerve Tissue Proteins; D000099153:Pentraxins