HMG-1 as a late mediator of endotoxin lethality in mice.
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.
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
H
H
Wang
O
O
Bloom
M
M
Zhang
J M
JM
Vishnubhakat
M
M
Ombrellino
J
J
Che
A
A
Frazier
H
H
Yang
S
S
Ivanova
L
L
Borovikova
K R
KR
Manogue
E
E
Faist
E
E
Abraham
J
J
Andersson
U
U
Andersson
P E
PE
Molina
N N
NN
Abumrad
A
A
Sama
K J
KJ
Tracey
D000818:Animals; D016470:Bacteremia / Q000097:blood*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D002460:Cell Line; D002478:Cells, Cultured; D019446:Endotoxemia / Q000097:blood*; D004731:Endotoxins / Q000097:blood / Q000633:toxicity*; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D007106:Immune Sera / Q000276:immunology; D007116:Immunization, Passive; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007928:Lethal Dose 50; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002352:Carrier Proteins; D004731:Endotoxins; D024243:HMGB1 Protein; D006609:High Mobility Group Proteins; D007106:Immune Sera; D007375:Interleukin-1; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma