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Published online before print November 29, 2006

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.0806540

Received for publication August 29, 2006.
Revised October 4, 2006.
Accepted for publication November 3, 2006.

Article

Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1

Daolin Tang ^*, Yongzhong Shi ^*, Rui Kang , Tong Li , Weimin Xiao ^*, Haichao Wang ^||, and Xianzhong Xiao ^*@

*Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, and Departments of Pediatrics and Rheumatology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; College of Optometry, University of Houston, Houston, Texas, USA; and ||Department of Emergency Medicine, North Shore University Hospital, New York University School of Medicine, Manhasset, New York, USA

^@ To whom correspondence should be addressed. E-mail: xianzhongxiao{at}xysm.net.

	Abstract

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-, IL-1, and IFN-) 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 (H₂O₂), 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), H₂O₂ induced HMGB1 cytoplasmic translocation and active release within 3-24 h. At higher concentrations (e.g., 0.25 mM), however, H₂O₂ exhibited cytotoxicity to macrophage and monocyte cell cultures and consequently, triggered active and passive HMGB1 release. In addition, H₂O₂ stimulated potential interaction of HMGB1 with a nuclear export factor, CRM1, in macrophage/monocyte cultures. Inhibitors specific for the JNK (SP600125) and MEK (PD98059), but not p38 MAPK (SB203580), abrogated H₂O₂-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.

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