A model of cellular responses of HMGB1 stimulation of endothelial cells.

HMGB1 secreted from stimulated monocyte-macrophages or released from necrotic cells can activate endothelial cells through ERK1/2 and 2 stress-activated MAPK pathways (JNK and p38), resulting in NF-κB and Sp1 binding to cellular response elements. Cell activation results in the release of a proinflammatory cytokine (TNFα) and chemokines (IL-8 and MCP-1), up-regulation of adhesion molecules (ICAM-1 and VCAM-1), and an HMGB1 receptor, RAGE. TNFα acts locally to amplify responses initiated by HMGB1. Secretion of regulators of fibrinolysis (tPA and PAI-1) results in the activation of plasmin that may limit HMGB1 responses by proteolytic degradation of HMGB1.