HMGB1 (high mobility group box chromosomal
protein 1), historically known as an abundant, nonhistone architectural chromosomal
protein, is extremely conserved across species. As a
nuclear protein,
HMGB1 stabilizes
nucleosomes and allows bending of
DNA that facilitates gene transcription. Unexpectedly, recent studies identified extracellular
HMGB1 as a potent macrophage-activating factor, signaling via the
receptor for advanced glycation end-products to induce inflammatory responses. It is released as a late mediator during
inflammation and participates in the pathogenesis of systemic
inflammation after the early mediator response has resolved.
HMGB1 occupies a critical role as a proinflammatory mediator passively released by necrotic but not apoptotic cells. Necrotic
Hmgb1(-/-) cells mediate minimal inflammatory responses. Stimulated macrophages actively secrete
HMGB1 to promote
inflammation and in turn, stimulate production of multiple, proinflammatory
cytokines.
HMGB1 mediates
endotoxin lethality,
acute lung injury,
arthritis induction, activation of macrophages, smooth muscle cell chemotaxis, and epithelial cell barrier dysfunction.
HMGB1 is structurally composed of three different domains: two homologous
DNA-binding sequences entitled box A and box B and a highly, negatively charged C terminus. The B box domain contains the proinflammatory
cytokine functionality of the molecule, whereas the A box region has an antagonistic, anti-inflammatory effect with therapeutic potential. Administration of highly purified, recombinant A box
protein or
neutralizing antibodies against
HMGB1 rescued mice from lethal
sepsis, even when initial treatment was delayed for 24 h after the onset of
infection, establishing a clinically relevant therapeutic window that is significantly wider than for other known
cytokines.