Cutting edge: high-mobility group box 1 preconditioning protects against liver ischemia-reperfusion injury.
High mobility group box 1 (HMGB1) is a NF released extracellularly as a late mediator of lethality in sepsis and as an early mediator of inflammation following injury. Here we demonstrate that in contrast to the proinflammatory role of HMGB1, preconditioning with HMGB1 results in protection following hepatic ischemia/reperfusion (I/R). Pretreatment of mice with HMGB1 significantly decreased liver damage after I/R. The protection observed in mice pretreated with HMGB1 was associated with a higher expression of IL-1R-associated kinase-M, a negative regulator of TLR4 signaling, compared with controls. We thus explored the possibility that HMGB1 preconditioning was mediated through TLR4 activation. HMGB1 preconditioning failed to provide protection in TLR4 mutant (C3H/HeJ) mice, but successfully reduced damage in TLR4 wild-type (C3H/HeOuj) mice. Our studies demonstrate that in contrast to the role of HMGB1 as an early mediator of inflammation and organ damage in hepatic I/R, HMGB1 preconditioning can be protective.
Izuishi
Kunihiko
K
Department of Surgery, University of Pittsburgh, PA 15213, USA.
Tsung
Allan
A
Jeyabalan
Geetha
G
Critchlow
Nathan D
ND
Li
Jianhua
J
Tracey
Kevin J
KJ
Demarco
Richard A
RA
Lotze
Michael T
MT
Fink
Mitchell P
MP
Geller
David A
DA
Billiar
Timothy R
TR
D000595:Amino Acid Sequence; D000818:Animals; D024243:HMGB1 Protein / Q000008:administration & dosage* / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D007275:Injections, Intravenous; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D015427:Reperfusion Injury / Q000201:enzymology / Q000378:metabolism* / Q000517:prevention & control*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology; D019172:Transplantation Conditioning / Q000379:methods*; D015854:Up-Regulation / Q000502:physiology
D024243:HMGB1 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases