Abstract
A nuclear protein, high mobility group box 1 (HMGB1), is released passively by necrotic cells and actively by macrophages/monocytes in response to exogenous and endogenous inflammatory stimuli. After binding to the receptor for advanced glycation end products (RAGE), or Toll-like receptor 4 (TLR4), HMGB1 activates macrophages/monocytes to express proinflammatory cytokines, chemokines, and adhesion molecules. Pharmacological suppression of its activities or release is protective against lethal endotoxemia and sepsis, establishing HMGB1 as a critical mediator of lethal systemic inflammation. In light of observations that many viruses (e.g., West Nile virus, Salmon anemia virus) can induce passive HMGB1 release, we propose a potential pathogenic role of HMGB1 in viral infectious diseases.