The specific interactions and functions of the HMGB1 DNA binding domains have been described. As noted above, the structure of HMGB1 contains two separate "boxes," the A-and B-boxes, each containing ~80 amino acids in an L-shaped fold, along with an acidic C-terminal tail (20) . These separate structural motifs appear to function differently when isolated from HMGB1. Several studies have identified the B-box domain as important for many of the proinflammatory properties of HMGB1 including cytokine release (22, 23) . In comparison, the A-box does not possess the pro-inflammatory properties of the B-box and instead competes with HMGB1 for binding sites leading to attenuation of the inflammatory cascade (24) .