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Published online before print November 29, 2006

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(Journal of Leukocyte Biology. 2007;81:741-747.)
© 2007 by Society for Leukocyte Biology

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^*,1

^* Laboratory of Shock, Department of Pathophysiology, Xiangya School of Medicine, and Departments of
Pediatrics and
Rheumatology, Xiangya Hospital, Central South University, Changsha, 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

¹ Correspondence: Department of Pathophysiology, Xiangya School of Medicine, Central South University, 110 Xiangya Road, Changsha, Hunan 410008, China. E-mail: xianzhongxiao{at}xysm.net

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, chromosome region maintenance (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.

Key Words: oxidative stress • nuclear protein • cytokine • CRm1 • MAPK

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