Abstract
High-mobility group box 1 (HMGB1) is a DNA-binding protein that also exhibits proinflammatory cytokine-like activity. HMGB1 is passively released by necrotic cells and also is actively secreted by immunostimulated macrophages, dendritic cells, and enterocytes. Although circulating HMGB1 levels are increased relative to healthy controls in patients with infections and severe sepsis, plasma or serum HMGB1 concentrations do not discriminate reliably between infected and uninfected critically ill patients. Nevertheless, administration of drugs that block HMGB1 secretion or of anti-HMGB1 neutralizing antibodies has been shown to ameliorate organ dysfunction and/or improve survival in numerous animal models of critical illness. Because HMGB1 tends to be released relatively late in the inflammatory response (at least in animal models of endotoxemia or sepsis), this protein is an attractive target for the development of new therapeutic agents for the treatment of patients with various forms of critical illness.
Highlights
Identified in the early 1960s [1], high-mobility group (HMG) proteins have been isolated and characterized from a wide variety of eukaryotic species, ranging from yeast to humans [2]
HMG proteins all have an unusual amino acid composition characterized by a high content of charged amino acids and a high content of proline [3]
One of the most important discoveries in the field of immunology during the past few years was the recognition that HMG box 1 (HMGB1) is a DNA-binding protein and a proinflammatory cytokine-like protein that fulfills ‘Koch’s postulates’ as a mediator of sepsis-induced lethality
Summary
Identified in the early 1960s [1], high-mobility group (HMG) proteins have been isolated and characterized from a wide variety of eukaryotic species, ranging from yeast to humans [2]. A number of agents have been shown to be capable of blocking HMGB1 secretion by immunostimulated cells, including various nicotinic cholinergic agonists [18,104]; stearoyl lysophosphatidylcholine [105]; ethyl pyruvate [19]; the serine protease inhibitor, nafamostat mesilate [86]; several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone) derived from a Chinese medicinal herb, danshen (Salvia miltiorrhiza) [92]; and the diuretic, ethacrynic acid, as well as other drugs that are known to be ‘phase 2 enzyme’ inducers [59] Some of these pharmacological agents, as well as various polyclonal neutralizing anti-HMGB1 antibodies, have been shown to ameliorate organ dysfunction and/or improve survival in various animal models of critical illness (see above). It is possible that approaches such as using hemoperfusion through a column packed with the LPSbinding agent, polymyxin B [106,107], can indirectly decrease circulating levels of HMGB1 by removing the upstream stimulus for secretion of the protein
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