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

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

Science (New York, N.Y.) (1999-07-10)

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

PMID10398600

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.