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Published online 28 March 2005 doi:10.1084/jem.20042614
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 7, 1135-1143
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ARTICLE

 The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion

Allan Tsung1, Rohit Sahai1, Hiroyuki Tanaka1, Atsunori Nakao1, Mitchell P. Fink1,2, Michael T. Lotze1, Huan Yang3, Jianhua Li3, Kevin J. Tracey3, David A. Geller1, and Timothy R. Billiar1

1 Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213
2 Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA 15213
3 Laboratory of Biomedical Science, North Shore University Hospital, New York University School of Medicine, Manhasset, NY 11030

CORRESPONDENCE Timothy R. Billiar: billiartr{at}msx.upmc.edu

High-mobility group box 1 (HMGB1) is a nuclear factor that is released extracellularly as a late mediator of lethality in sepsis as well as after necrotic, but not apoptotic, death. Here we demonstrate that in contrast to the delayed role of HMGB1 in the systemic inflammation of sepsis, HMGB1 acts as an early mediator of inflammation and organ damage in hepatic ischemia reperfusion (I/R) injury. HMGB1 levels were increased during liver I/R as early as 1 h after reperfusion and then increased in a time-dependent manner up to 24 h. Inhibition of HMGB1 activity with neutralizing antibody significantly decreased liver damage after I/R, whereas administration of recombinant HMGB1 worsened I/R injury. Treatment with neutralizing antibody was associated with less phosphorylation of c-Jun NH2-terminal kinase and higher nuclear factor–{kappa}B DNA binding in the liver after I/R. Toll-like receptor 4 (TLR4)-defective (C3H/Hej) mice exhibited less damage in the hepatic I/R model than did wild-type (C3H/HeOuj) mice. Anti-HMGB1 antibody failed to provide protection in C3H/Hej mice, but successfully reduced damage in C3H/Ouj mice. Together, these results demonstrate that HMGB1 is an early mediator of injury and inflammation in liver I/R and implicates TLR4 as one of the receptors that is involved in the process.

Abbreviations used: ERK, extracellular signal-regulated kinase; HMGB1, high-mobility group box 1; iNOS, inducible NO synthase; I/R, ischemia/reperfusion; JNK, c-Jun NH2-terminal kinase; MAP, mitogen-activated protein; rHMGB1, recombinant HMGB1; sALT, serum alanine aminotransferase; TLR, Toll-like receptor.


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