Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1.
High mobility group box 1 (HMGB1) can be actively secreted by macrophages/monocytes in response to exogenous and endogenous inflammatory stimuli (such as bacterial endotoxin, TNF-alpha, IL-1, and IFN-gamma) or passively released by necrotic cells and mediates innate and adaptive inflammatory responses to infection and injury. Here, we demonstrated that a reactive oxygen species, hydrogen peroxide (H(2)O(2)), induces active and passive HMGB1 release from macrophage and monocyte cultures in a time- and dose-dependent manner. At nontoxic doses (e.g., 0.0125-0.125 mM), H(2)O(2) induced HMGB1 cytoplasmic translocation and active release within 3-24 h. At higher concentrations (e.g., 0.25 mM), however, H(2)O(2) exhibited cytotoxicity to macrophage and monocyte cell cultures and consequently, triggered active and passive HMGB1 release. In addition, H(2)O(2) stimulated potential interaction of HMGB1 with a nuclear export factor, chromosome region maintenance (CRM1), in macrophage/monocyte cultures. Inhibitors specific for the JNK (SP600125) and MEK (PD98059), but not p38 MAPK (SB203580), abrogated H(2)O(2)-induced, active HMGB1 release. Together, these data establish an important role for oxidative stress in inducing active HMGB1 release, potentially through a MAPK- and CRM1-dependent mechanism.
Tang
Daolin
D
Department of Pathophysiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China.
Shi
Yongzhong
Y
Kang
Rui
R
Li
Tong
T
Xiao
Weimin
W
Wang
Haichao
H
Xiao
Xianzhong
X
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D024243:HMGB1 Protein / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D028884:Karyopherins / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D017382:Reactive Oxygen Species / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D000097606:Exportin 1 Protein
D000873:Anthracenes; D005419:Flavonoids; D024243:HMGB1 Protein; D006861:Hydrogen Peroxide; D028884:Karyopherins; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D000097606:Exportin 1 Protein; C432165:pyrazolanthrone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one