Dual roles for HMGB1: DNA binding and cytokine

Effective therapies against overwhelming Gram-negative bacteremia, or sepsi s, have eluded successful development. The discovery that tumor necrosis fa ctor (TNF), a host-derived inflammatory mediator, was both necessary and su fficient to recapitulate Gram-negative sepsis raised cautious optimism for developing a targeted therapeutic. However, the rapid kinetics of the TNF r esponse to infection defined an extremely narrow window of opportunity duri ng which anti-TNF therapeutics could be successfully administered. HMGB1 wa s previously studied as a DNA-binding protein involved in DNA replication, repair. and transcription; and as a membrane-associated protein that mediat es neurite outgrowth. A decade-long search has culminated in our identifica tion of HMGB1 as a late mediator of endotoxemia. HMGB1 is released by macro phages upon exposure to endotoxin, activates many other proinflammatory med iators, and is lethal to otherwise healthy animals. Elevated levels of HMGB 1 are observed in the serum of patients with sepsis, and the highest levels were found in those patients that died. The delayed kinetics of HMGB1 rele ase indicate that it may be useful to target this toxic cytokine in the dev elopment of future therapies.