HMG-1 as a late mediator of endotoxin lethality in mice

H Wang; O Bloom; M Zhang; J M Vishnubhakat; M Ombrellino; J Che; A Frazier; H Yang; S Ivanova; L Borovikova; K R Manogue; E Faist; E Abraham; J Andersson; U Andersson; P E Molina; N N Abumrad; A Sama; K J Tracey

doi:10.1126/science.285.5425.248

HMG-1 as a late mediator of endotoxin lethality in mice

Science. 1999 Jul 9;285(5425):248-51. doi: 10.1126/science.285.5425.248.

Authors

Affiliation

¹ Department of Emergency Medicine and Department of Surgery, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA. [email protected]

PMID: 10398600
DOI: 10.1126/science.285.5425.248

Abstract

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

MeSH terms

Animals
Bacteremia / blood*
Carrier Proteins / genetics
Carrier Proteins / immunology
Carrier Proteins / metabolism*
Carrier Proteins / toxicity
Cell Line
Cells, Cultured
Endotoxemia / blood*
Endotoxins / blood
Endotoxins / toxicity*
HMGB1 Protein
High Mobility Group Proteins / genetics
High Mobility Group Proteins / immunology
High Mobility Group Proteins / metabolism*
High Mobility Group Proteins / toxicity
Humans
Immune Sera / immunology
Immunization, Passive
Interferon-gamma / pharmacology
Interleukin-1 / pharmacology
Lethal Dose 50
Leukocytes, Mononuclear / metabolism
Lipopolysaccharides / toxicity
Macrophages / metabolism*
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
RNA, Messenger / genetics
RNA, Messenger / metabolism
Time Factors
Tumor Necrosis Factor-alpha / pharmacology

Substances

Carrier Proteins
Endotoxins
HMGB1 Protein
High Mobility Group Proteins
Immune Sera
Interleukin-1
Lipopolysaccharides
RNA, Messenger
Tumor Necrosis Factor-alpha
Interferon-gamma