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.

In:Science (New York, N.Y.): American Association for the Advancement of Science (AAAS)285:5425, s. 248-2510036-80751095-9203

By the author/editor: Wang, HC; Bloom, O; Zhang, MH; Vishnubhakat, JM; Ombrellino, M; Che, JT; show more...; Frazier, A; Yang, H; Ivanova, S; Borovikova, L; Manogue, KR; Faist, E; Abraham, E; Andersson, J; Andersson, U; Molina, PE; Abumrad, NN; Sama, A; Tracey, KJ; show less...

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