673Review Article The Cytokine Activity of HMGB1- Extracellular Escape of the Nuclear Protein

High mobility group box 1 (HMGB1), a mobile chromatin protein, passively leaks from necrotic cells and signals neighboring cells that tissue damage has occurred. Resting, non-activated inflammatory cells such as monocytes or macrophages contain HMGB1 in the nuclear compartment. When activated by lipopolysaccharide or inflammatory cytokines, they actively translocate the nuclear HMGB1 into the cyto-plasm; HMGB1 is then exocytosed. At least one receptor for extracel-lular HMGB1 has been identified. HMGB1 acts as a mediator of sys-tematic inflammation; it causes different cells to divide, migrate or elic-it an immune response. Here, we give an abridged review of the cytokine activity of HMGB1, including its secretion mechanism, the putative signal transduction pathways, and its role in several inflamma-tory diseases. Finally, we cite a few examples in which therapeutic administration of HMGB1 antagonists rescued mice from lethal sepsis, arthritis and liver damage. The new findings of HMGB1 as a cytokine provide a better understanding of inflammatory diseases, establishing a clinically relevant therapeutic target that is significantly more efficient than other known cytokines. (Chan