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GROWTH, DIFFERENTIATION, AND APOPTOSIS

The extracellular release of HMGB1 during apoptotic cell death

Division of Rheumatology and Immunology, Duke University Medical Center, and Medical Research Service, Durham Veterans Affairs Hospital, Durham, North Carolina

Submitted 12 December 2005 ; accepted in final form 17 July 2006

High mobility group box 1 protein (HMGB1) is a non-histone nuclear protein with dual function. Inside the cell, HMGB1 binds DNA and regulates transcription, whereas outside the cell, it serves as a cytokine and mediates the late effects of LPS. The movement of HMGB1 into the extracellular space has been demonstrated for macrophages stimulated with LPS as well as cells undergoing necrosis but not apoptosis. The differential release of HMGB1 during death processes could reflect the structure of chromatin in these settings as well as the mechanisms for HMGB1 translocation. Since apoptotic cells can release some nuclear molecules such as DNA to which HMGB1 can bind, we therefore investigated whether HMGB1 release can occur during apoptosis as well as necrosis. For this purpose, Jurkat cells were treated with chemical inducers of apoptosis (staurosporine, etoposide, or camptothecin), and HMGB1 release into the medium was assessed by Western blotting. Results of these experiments indicate that HMGB1 appears in the media of apoptotic Jurkat cells in a time-dependent manner and that this release can be reduced by Z-VAD-fmk. Panc-1 and U937 cells treated with these agents showed similar release. In addition, HeLa cells induced to undergo apoptosis showed HMGB1 release. Furthermore, we showed using confocal microscopy that HMGB1 and DNA change their nuclear location in Jurkat cells undergoing apoptosis. Together, these studies indicate that HMGB1 release can occur during the course of apoptosis as well as necrosis and suggest that the release process may vary with cell type.

necrosis; cytokines; inflammation

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