Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0306180 on September 11, 2006

Published online before print September 11, 2006
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(Journal of Leukocyte Biology. 2007;81:59-66.)
© 2007 by Society for Leukocyte Biology

High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin

De Yang*,{dagger},1, Qian Chen*, Huan Yang{ddagger}, Kevin J. Tracey{ddagger}, Michael Bustin§ and Joost J. Oppenheim*

* Laboratory of Molecular Immunoregulation, Center for Cancer Research, and
{dagger} Basic Research Program, SAIC-Frederick, Inc., National Cancer Institute at Frederick, Maryland, USA;
{ddagger} Laboratory of Biomedical Science, North Shore–Long Island Jewish Research Institute, Manhasset, New York, USA; and
§ Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

1Correspondence: SAIC-Frederick, Basic Research Program, Rm. 31-19/Bldg. 560, 1050 Boyles Street, Frederick, MD 21702, USA. E-mail: dyang{at}ncifcrf.gov

ABSTRACT

High mobility group box-1 (HMGB1) protein is a nonhistone, DNA-binding protein that plays a critical role in regulating gene transcription. Recently, HMGB1 has also been shown to act as a late mediator of endotoxic shock and to exert a variety of proinflammatory, extracellular activities. Here, we report that HMGB1 simultaneously acts as a chemoattractant and activator of dendritic cells (DCs). HMGB1 induced the migration of monocyte-derived, immature DCs (Mo-iDCs) but not mature DCs. The chemotactic effect of HMGB1 on iDCs was pertussis toxin-inhibitable and also inhibited by antibody against the receptor of advanced glycation end products (RAGE), suggesting that HMGB1 chemoattraction of iDCs is mediated by RAGE in a Gi protein-dependent manner. In addition, HMGB1 treatment of Mo-iDCs up-regulated DC surface markers (CD80, CD83, CD86, and HLA-A,B,C), enhanced DC production of cytokines (IL-6, CXCL8, IL-12p70, and TNF-{alpha}), switched DC chemokine responsiveness from CCL5-sensitive to CCL21-sensitive, and acquired the capacity to stimulate allogeneic T cell proliferation. Based on its dual DC-attracting and -activating activities as well as its reported capacity to promote an antigen-specific immune response, we consider HMGB1 to have the properties of an immune alarmin.

Key Words: RAGE • chemotaxis • maturation • HMGB1




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