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PMID:12765338

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Citation

Li, J, Kokkola, R, Tabibzadeh, S, Yang, R, Ochani, M, Qiang, X, Harris, HE, Czura, CJ, Wang, H, Ulloa, L, Wang, H, Warren, HS, Moldawer, LL, Fink, MP, Andersson, U, Tracey, KJ and Yang, H Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol. Med. 9:37-45

Abstract

High mobility group box 1 (HMGB), a ubiquitous DNA-binding protein, has been implicated as a proinflammatory cytokine and late mediator of lethal endotoxemia. HMGB1 is released by activated macrophages. It amplifies and extends the inflammatory response by inducing cytokine release and mediating acute lung injury, anorexia, and the inflammatory response to tissue necrosis. The kinetics of HMGB1 release provide a wide therapeutic window for endotoxemia because extracellular levels of HMGB1 begin to increase 12 to 24 h after exposure to inflammatory stimuli. Here, we demonstrate that a DNA-binding domain of HMGB1, the B box, recapitulates the cytokine activity of full length HMGB1 and efficiently activates macrophages to release tumor necrosis factor (TNF) and other proinflammatory cytokines. Truncation of the B box revealed that the TNF-stimulating activity localizes to 20 amino acids (HMGB1 amino acids 89 to 108). Passive immunization of mice with antibodies raised against B box conferred significant protection against lethal endotoxemia or sepsis, induced by cecal perforation. These results indicate that a proinflammatory domain of HMGB1 maps to the highly conserved DNA-binding B box, making this primary sequence a suitable target in the design of therapeutics.

Links

PubMed PMC1430376

Keywords

Animals; Cell Nucleus/metabolism; Cytokines/metabolism; DNA Primers/chemistry; Electrophoretic Mobility Shift Assay; Endotoxemia/prevention & control; Glutathione Transferase/metabolism; HMGB1 Protein/chemistry; HMGB1 Protein/physiology; Immunization, Passive; Lipopolysaccharides/pharmacology; Macrophage Activation; Macrophages/immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Peptide Fragments/immunology; Peptide Fragments/metabolism; Polymerase Chain Reaction; Rabbits; Sepsis/immunology; Tumor Necrosis Factor-alpha/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:HMGB1

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:0032755: positive regulation of interleukin-6 production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:0032732: positive regulation of interleukin-1 production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:1990774: tumor necrosis factor secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:0050716: positive regulation of interleukin-1 secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:2000778: positive regulation of interleukin-6 secretion

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:0043410: positive regulation of MAPK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:HMGB1

involved_in

GO:0046330: positive regulation of JNK cascade

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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