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 tria ls, possibly because these cytokines are early mediators in pathogenesis, H ere 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 rel eased by cultured macrophages more than 8 hours after stimulation with endo toxin, 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 i tself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.