Publication Date:
1999-07-10
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, H -- Bloom, O -- Zhang, M -- Vishnubhakat, J M -- Ombrellino, M -- Che, J -- Frazier, A -- Yang, H -- Ivanova, S -- Borovikova, L -- Manogue, K R -- Faist, E -- Abraham, E -- Andersson, J -- Andersson, U -- Molina, P E -- Abumrad, N N -- Sama, A -- Tracey, K J -- New York, N.Y. -- Science. 1999 Jul 9;285(5425):248-51.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Emergency Medicine and Department of Surgery, North Shore University Hospital-New York University School of Medicine, Manhasset, NY 11030, USA. hwang@picower.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/10398600" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bacteremia/*blood
;
Carrier Proteins/genetics/immunology/*metabolism/toxicity
;
Cell Line
;
Cells, Cultured
;
Endotoxemia/*blood
;
Endotoxins/blood/*toxicity
;
HMGB1 Protein
;
High Mobility Group Proteins/genetics/immunology/*metabolism/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/metabolism
;
Time Factors
;
Tumor Necrosis Factor-alpha/pharmacology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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