High mobility group box protein 1: an endogenous signal for dendritic cell maturation and Th1 polarization.
High mobility group box protein 1 (HMGB1), a DNA binding nuclear and cytosolic protein, is a proinflammatory cytokine released by monocytes and macrophages. This study addressed the hypothesis that HMGB1 is an immunostimulatory signal that induces dendritic cell (DC) maturation. We show that HMGB1, via its B box domain, induced phenotypic maturation of DCs, as evidenced by increased CD83, CD54, CD80, CD40, CD58, and MHC class II expression and decreased CD206 expression. The B box caused increased secretion of the proinflammatory cytokines IL-12, IL-6, IL-1alpha, IL-8, TNF-alpha, and RANTES. B box up-regulated CD83 expression as well as IL-6 secretion via a p38 MAPK-dependent pathway. In the MLR, B box-activated DCs acted as potent stimulators of allogeneic T cells, and the magnitude of the response was equivalent to DCs activated by exposure to LPS, nonmethylated CpG oligonucleotides, or CD40L. Furthermore, B box induced secretion of IL-12 from DCs as well as IL-2 and IFN-gamma secretion from allogeneic T cells, suggesting a Th1 bias. HMGB1 released by necrotic cells may be a signal of tissue or cellular injury that, when sensed by DCs, induces and/or enhances an immune reaction.
Messmer
Davorka
D
Laboratory of Experimental Immunology, North Shore-LIJ Research Institute, 350 Community Drive, Manhasset, NY 11030, USA. dmessmer@nshs.edu
Yang
Huan
H
Telusma
Gloria
G
Knoll
Faye
F
Li
Jianhua
J
Messmer
Bradley
B
Tracey
Kevin J
KJ
Chiorazzi
Nicholas
N
D000595:Amino Acid Sequence; D015703:Antigens, CD; D016764:Cell Polarity; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000502:physiology*; D024243:HMGB1 Protein / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D018417:Th1 Cells / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases; D000097802:CD83 Antigen
D015703:Antigens, CD; D018925:Chemokines; D016207:Cytokines; D024243:HMGB1 Protein; D007136:Immunoglobulins; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D048051:p38 Mitogen-Activated Protein Kinases; D000097802:CD83 Antigen