RAPID COMMUNICATION Hydrogen peroxide stimulates macrophages and monocytes to actively release HMGB1

Abstract: High mobility group box 1 (HMGB1) can be actively secreted by macrophages/mono-cytes 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 spe-cies, 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 translo-cation and active release within 3–24 h. At higher concentrations (e.g., 0.25 mM), however, H2O2 exhibited cytotoxicity to macrophage and mono-cyte cell cultures and consequently, triggered ac-tive and passive HMGB1 release. In addition, H2O2 stimulated potential interaction of HMGB1 with a nuclear export factor, chromosome region maintenance (CRM1), in macrophage/monocyte cul-tures. 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- an