High mobility group box-1 protein induces the migration and activation of human dendritic cells and acts as an alarmin.
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.
Yang
De
D
Laboratory of Molecular Immunoregulation, Center for Cancer Research, and Basic Research Program, Rm. 31-19/Bldg. 560, 1050 Boyles Street, Frederick, MD 21702, USA. dyang@ncifcrf.gov
Chen
Qian
Q
Yang
Huan
H
Tracey
Kevin J
KJ
Bustin
Michael
M
Oppenheim
Joost J
JJ
D002454:Cell Differentiation; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000494:pharmacology*; D002633:Chemotaxis; D003713:Dendritic Cells / Q000276:immunology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D009000:Monocytes / Q000502:physiology; D037342:Pertussis Toxin / Q000494:pharmacology; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology
D002630:Chemotactic Factors; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D037342:Pertussis Toxin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go