Monoclonal Hmgb1 Antibodies Protect Against Sepsis Lethality in Mice

Yang, H. J.; Qin, Shixin; Kumar, Anjali; Ochani, Mahendar; Ochani, Kanta; Amella, C. A.; Czura, Christopher J.; LaRosa, Greg; Tracey, Kevin J.

doi:10.1097/00024382-200403001-00509

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“…Delayed treatment with anti-HMGB1 antibodies or other antagonists (A box or ethyl pyruvate) dose-dependently rescued mice from lethal sepsis induced by cecal perforation, and treatment was effective even when the first dose was given at 24 h after the cecal ligation and puncture surgery [8,73]. Recently developed anti-HMGB1 monoclonal antibodies confirmed these findings [74]. In vitro studies showed that A box competitively inhibits 125 I-labeled HMGB1 cell-surface binding and attenuates HMGB1-induced proinflammatory cytokine release in macrophage-like RAW 264.7 cells [8], and ethyl pyruvate specifically attenuates LPS-induced HMGB1 release and inhibits p38 MAPK and NF-B activation in macrophage cultures [73].…”

Section: Anti-hmgb1 Treatment In Inflammatory Diseasesmentioning

confidence: 77%

The cytokine activity of HMGB1

Yang

Wang

Czura

et al. 2005

Journal of Leukocyte Biology

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High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein present in the nuclei and cytoplasm of nearly all cell types. We recently discovered that HMGB1 is secreted into the extracellular milieu and acts as a proinflammatory cytokine. Administration of HMGB1 to normal animals causes inflammatory responses, including fever, weight loss and anorexia, acute lung injury, epithelial barrier dysfunction, arthritis, and death. Anti-HMGB1 treatment, with antibodies or specific antagonists, rescues mice from lethal endotoxemia or sepsis and ameliorates the severity of collagen-induced arthritis and endotoxin-induced lung injury. Here, we give an abridged review of the cytokine activity of HMGB1, its secretion and release into the extracellular milieu, the putative signal transduction pathways, including interaction with cell-surface receptors and intracellular signaling, and its role in several inflammatory diseases. Finally, the therapeutic potential of blocking HMGB1 in the treatment of inflammatory diseases is discussed. J. Leukoc. Biol. 78: 1-8; 2005.

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