The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion.
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 NH(2)-terminal kinase and higher nuclear factor-kappaB 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.
Tsung
Allan
A
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Sahai
Rohit
R
Tanaka
Hiroyuki
H
Nakao
Atsunori
A
Fink
Mitchell P
MP
Lotze
Michael T
MT
Yang
Huan
H
Li
Jianhua
J
Tracey
Kevin J
KJ
Geller
David A
DA
Billiar
Timothy R
TR
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D024243:HMGB1 Protein / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D051197:Toll-Like Receptor 4
D000906:Antibodies; D024243:HMGB1 Protein; D016328:NF-kappa B; D011956:Receptors, Cell Surface; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048031:JNK Mitogen-Activated Protein Kinases