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The discovery of tumor necrosis factor (TNF) as a necessary and sufficient mediator of systemic inflammation started a new field of research to rationally modulate cytokine responses to therapeutic advantage. However, the early kinetics of the TNF response during infection defined an extremely narrow window of opportunity during which anti-TNF therapeutics are efficacious, hampering clinical development for severe sepsis. Because death from severe sepsis often occurs as a late phenomenon, we began a search began for putative "late" mediators that could be targeted after the onset of infection. We have now identified high mobility group box-1 (HMGB1) as a late mediator of endotoxemia and sepsis. HMGB1 is released by activated macrophages, induces the release of other proinflammatory mediators, and mediates lethality when overexpressed. Administration of anti-HMGB1 antibodies inhibit systemic inflammation, even in established cases, because HMGB1 activity is elevated at significantly later time points than TNF or interleukin-1. It will now be important to determine whether this wider window of activity can be translated into therapeutic advantage for human inflammatory disease.

High Mobility Group Box–1 as a Therapeutic Target Downstream of Tumor Necrosis Factor