Interferon regulatory factor 1 mediates acetylation and release of high mobility group box 1 from hepatocytes during murine liver ischemia-reperfusion injury.
Damage-associated molecular patterns (DAMPs) initiate inflammatory pathways that are common to both sterile and infectious processes. The DAMP, high-mobility group box 1 (HMGB1), and the transcription factor, interferon regulatory factor 1 (IRF-1), have been independently associated as key players in ischemia-reperfusion (I/R) injury. Our study demonstrates that IRF-1 contributes to hepatocellular release of HMGB1 and further that IRF-1 is a necessary component of HMGB1 release in response to hypoxia or after liver I/R. We also link the nuclear upregulation of IRF-1 to the presence of functional Toll-like receptor 4 (TLR4), a pattern recognition receptor also important in sterile and infectious processes. Using IRF-1 chimeric mice, we show that IRF-1 upregulation in hepatic parenchymal cells, and not in the bone marrow-derived immune cells, is responsible for HMGB1 release during ischemic liver injury. Finally, our study also demonstrates a role for IRF-1 in modulating the acetylation status and subsequent release of HMGB1 through histone acetyltransferases. We found that serum HMGB1 is acetylated after liver I/R and that this process was dependent on IRF-1. Additionally, liver I/R induced a direct association of IRF-1 and the nuclear histone acetyltransferase enzyme p300. Together, these findings suggest that I/R-induced release of acetylated HMGB1 is a process that is dependent on TLR4-mediated upregulation of IRF-1.
Dhupar
Rajeev
R
Department of Surgery, and †Cell Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Klune
John R
JR
Evankovich
John
J
Cardinal
Jon
J
Zhang
Matthew
M
Ross
Mark
M
Murase
Noriko
N
Geller
David A
DA
Billiar
Timothy R
TR
Tsung
Allan
A
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D047468:Immunoprecipitation; D050856:Interferon Regulatory Factor-1 / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D015427:Reperfusion Injury / Q000097:blood / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
D024243:HMGB1 Protein; D050856:Interferon Regulatory Factor-1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4