High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis

High mobility group box chromosomal protein 1 (HMGB-1), a DNA binding protein, is an intracellular protein that facilitates DNA bending, stabilizes nucleosome formation, and modulates the interactions of regulatory molecules with their targets. Recent evidence has revealed that HMGB-1 is also a cytokine, because it 1) is released from activated monocyte/macrophages, 2) mediates delayed endotoxin lethality, 3) activates macrophages, 4) stimulates inflammation in vivo, and 5) is a therapeutic target in diverse animal models of inflammatory disease (1–4). Our review accompanies the report by Taniguchi and colleagues (5), in this issue of Arthritis & Rheumatism, of a new study of HMGB-1 in the pathogenesis of arthritis. We summarize here the history of research on HMGB-1 as an intracellular protein and discuss in more detail a rapidly growing body of evidence that implicates HMGB-1 as a cytokine that can mediate inflammation and arthritis. Some important new findings are highlighted, and a series of observations that warrant additional study are raised. The molecular basis of the cytokine activity of HMGB-1 and the biochemistry of this potentially important therapeutic target are discussed.