HMGB1 is a member of the high-mobility group
protein superfamily that has been widely studied as
nuclear proteins that bind
DNA, stabilize
nucleosomes and facilitate gene transcription. A series of recent discoveries revealed a
cytokine activity of
HMGB1, that when secreted into the extracellular milieu, mediates downstream inflammatory responses in
endotoxemia,
arthritis and
sepsis.
HMGB1 is properly defined as a
cytokine because it stimulates proinflammatory responses in monocytes/macrophages, is produced during inflammatory responses in vivo in standardized models of systemic and local
inflammation, mediates delayed
endotoxin lethality, and is required for the full expression of
inflammation in animal models of
endotoxemia,
sepsis and
arthritis.
HMGB1 is either actively secreted by monocytes/macrophages or passively released from necrotic cells from any tissue. These pathways are central for the biology of
HMGB1 as a
cytokine, since they provide key mechanisms that integrate the inflammatory response to infectious and non-infectious cell
injuries. Receptor signal transduction of
HMGB1 occurs in part through the
receptor for advanced glycation end-products (RAGE) expressed on monocytes/macrophages, endothelial cells, neurons and smooth-muscle cells.
HMGB1 is a late-acting
cytokine, because it first appears in the extracellular milieu 8-12 h after the initial macrophage response to proinflammatory stimuli. Knowledge of the
cytokine role of
HMGB1 has implications for understanding downstream
cytokine cascades, regulation of delayed innate immune responses and targeting treatment towards these processes. Effectiveness of
delayed treatment with
HMGB1 blockade up to 24 h after induction of experimental
sepsis offers a unique window of opportunities to allow rescue from lethal
sepsis.