HMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Haichao Wang et al.
Science 285, 248
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 efÞcacy in clinical trials, possibly because
these cytokines are early mediators in pathogenesis. Here a potential late
mediator of lethality is identiÞed and characterized in a mouse model. High
mobility groupÐ1 (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.
HMG-1 peptide antibody was generate at Bio-Synthesis.