• Steven G Friedman, Christopher J Czura, and Kevin J Tracey.
• Division of Vascular Surgery, North Shore University Hospital, North Shore-Long Island Jewish Research Institute, Manhasset, New York, USA.
• Curr Opin Clin Nutr Metab Care. 2003 May 1; 6 (3): 283-7.

Purpose Of ReviewProducts of infection, ischemia, and injury stimulate the innate immune system to release proinflammatory cytokines, which act locally to activate specific cellular immune responses and initiate recovery. In pathological cases, however, cytokines are released systemically, resulting in progressive tissue injury, hypotension, organ dysfunction, or death. Observations that animals frequently succumb to systemic inflammation long after the peak activity of tumor necrosis factor and interleukin-1beta suggest that later-acting, downstream inflammatory factors can mediate the pathological sequelae of lethal systemic inflammation. Here, the authors review evidence that the chromosomal protein high mobility group box 1 is a late-acting, downstream mediator of pathological inflammation.Recent FindingsHigh mobility group box 1 recently has been identified as a proinflammatory cytokine with significantly delayed release kinetics, as compared with tumor necrosis factor and interleukin-1beta, in animal models of lethal systemic inflammation induced by endotoxin or peritonitis. Administration of exogenous high mobility group box 1 induces acute lung injury, intestinal barrier dysfunction, and lethal systemic inflammatory responses. Its functional cytokine domain has been mapped to the DNA-binding B box, providing structural information that may be useful in the rational design of new therapeutics that target the protein's activity.SummarySeveral high mobility group box 1 antagonists have recently been identified. These inhibitors may prove effective in a significantly wider therapeutic window than has been available for previous anti-cytokine strategies, because high mobility group box 1 appears in serum with a significantly delayed kinetics as compared with other cytokines.

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