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-α, IL-1, and IFN-γ) 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, 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.

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