Oxidation of HMGB1 causes attenuation of its pro-inflammatory activity and occurs during liver ischemia and reperfusion

High mobility group box 1 (HMGB1) is a nuclear transcription factor. Once HMGB1 is released by damaged cells or activated immune cells, it acts as danger molecule and triggers the inflammatory signaling cascade. Currently, evidence is accumulating that posttranslational modifications such as oxidati...

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Bibliographic Details
Published in:PloS one 2012-04, Vol.7 (4), p.e35379-e35379
Main Authors: Liu, Anding, Fang, Haoshu, Dirsch, Olaf, Jin, Hao, Dahmen, Uta
Format: Article
Language:English
Subjects:
Animals
Attenuation
Biology
Blotting, Western
Cell culture
Chromosomal proteins
Cold storage
Cryopreservation
Cytokines
Effluents
Electrophoresis, Polyacrylamide Gel
Enzyme-Linked Immunosorbent Assay
Grafting
Grafts
Hazards
High mobility group proteins
HMGB1 protein
HMGB1 Protein - blood
HMGB1 Protein - metabolism
HMGB1 Protein - pharmacology
Hospitals
Hostages
Hydrogen peroxide
Immune system
Immunohistochemistry
Immunoprecipitation
Inflammation
Interleukins
Ischemia
Liver
Liver diseases
Liver Diseases - metabolism
Liver Transplantation
Liver transplants
Macrophages
Macrophages, Peritoneal - metabolism
Male
Medicine
Metabolism
Oxidation
Oxidation-reduction reactions
Polymerase Chain Reaction
Post-translation
Proteins
Rats
Reperfusion
Reperfusion Injury - metabolism
Rodents
Signaling
Syngeneic grafts
Translocation
Transplantation
Tumor necrosis factor-TNF
Tumor necrosis factor-α
Vascular surgery
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Summary:High mobility group box 1 (HMGB1) is a nuclear transcription factor. Once HMGB1 is released by damaged cells or activated immune cells, it acts as danger molecule and triggers the inflammatory signaling cascade. Currently, evidence is accumulating that posttranslational modifications such as oxidation may modulate the pro-inflammatory potential of danger signals. We hypothesized that oxidation of HMGB1 may reduce its pro-inflammatory potential and could take place during prolonged ischemia and upon reperfusion.Liver grafts were cold preserved for 24 h and flushed with saline in hourly intervals to collect the effluent. Liver grafts, cold-preserved for 6 h, were transplanted into syngeneic recipients to obtain serum and liver samples 24 h after initiation of reperfusion. Addition of the effluent to a macrophage culture induced the synthesis of tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6. The stimulatory activity of graft effluent was reduced after depletion of HMGB1 via immunoprecipitation. Oxidation of the effluent HMGB1 using H(2)O(2) attenuated its stimulatory activity as well. Liver transplantation of cold preserved grafts caused HMGB1 translocation and release as determined by immunohistochemistry and ELISA-assay, respectively. Using Western blot with non-reducing conditions revealed the presence of oxidized HMGB1 in liver samples obtained after 12 h and in effluent samples after 16 h of cold preservation as well as in liver and serum samples obtained 24 h after reperfusion.These observations confirm that post-translational oxidation of HMGB1 attenuates its pro-inflammatory activity. Oxidation of HMGB1 as induced during prolonged ischemia and by reoxygenation during reperfusion in vivo might also attenuate its pro-inflammatory activity. Our findings also call for future studies to investigate the mechanism of the inhibitory effect of oxidized HMGB1 on the pro-inflammatory potential.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0035379