Activation of gene expression in human neutrophils by high mobility group box 1 protein.
High mobility group box 1 (HMGB1) protein, a DNA binding protein that stabilizes nucleosomes and facilitates transcription, was recently identified as a late mediator of endotoxin lethality. High serum HMGB1 levels in patients with sepsis are associated with increased mortality, and administration of HMGB1 produces acute inflammation in animal models of lung injury and endotoxemia. Neutrophils occupy a critical role in mediating the development of endotoxemia-associated acute lung injury, but previously it was not known whether HMGB1 could influence neutrophil activation. In the present experiments, we demonstrate that HMGB1 increases the nuclear translocation of NF-kappaB and enhances the expression of proinflammatory cytokines in human neutrophils. These proinflammatory effects of HMGB1 in neutrophils appear to involve the p38 MAPK, phosphatidylinositol 3-kinase/Akt, and ERK1/2 pathways. The mechanisms of HMGB1-induced neutrophil activation are distinct from endotoxin-induced signals, because HMGB1 leads to a different profile of gene expression, pattern of cytokine expression, and kinetics of p38 activation compared with LPS. These findings indicate that HMGB1 is an effective stimulus of neutrophil activation that can contribute to development of a proinflammatory phenotype in diseases characterized by excessively high levels of HMGB1.
Park
Jong Sung
JS
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Arcaroli
John
J
Yum
Ho-Kee
HK
Yang
Huan
H
Wang
Haichao
H
Yang
Kuang-Yao
KY
Choe
Kang-Hyeon
KH
Strassheim
Derek
D
Pitts
Todd M
TM
Tracey
Kevin J
KJ
Abraham
Edward
E
D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D024243:HMGB1 Protein / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010770:Phosphotransferases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D018925:Chemokines; D016207:Cytokines; D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D012333:RNA, Messenger; D010770:Phosphotransferases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases