Abstract
High mobility group box 1 (HMGB1), 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 37-45 |
| Number of pages | 9 |
| Journal | Molecular Medicine |
| Volume | 9 |
| Issue number | 1-2 |
| State | Published - Jan 1 2003 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Genetics(clinical)
- Genetics
- Molecular Medicine
- Molecular Biology
Cite this
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Structural basis for the proinflammatory cytokine activity of high mobility group box 1. / Li, Jianhua; Kokkola, Riikka; Tabibzadeh, Siamak; Yang, Runkuan; Ochani, Mahendar; Qiang, Xiaoling; Harris, Helena E.; Czura, Christopher J.; Wang, Haichao; Ulloa, Luis; Wang, Hong; Warren, H. Shaw; Moldawer, Lyle L.; Fink, Mitchell P.; Andersson, Ulf; Tracey, Kevin J.; Yang, Huan.
In: Molecular Medicine, Vol. 9, No. 1-2, 01.01.2003, p. 37-45.Research output: Contribution to journal › Article
TY - JOUR
T1 - Structural basis for the proinflammatory cytokine activity of high mobility group box 1
AU - Li, Jianhua
AU - Kokkola, Riikka
AU - Tabibzadeh, Siamak
AU - Yang, Runkuan
AU - Ochani, Mahendar
AU - Qiang, Xiaoling
AU - Harris, Helena E.
AU - Czura, Christopher J.
AU - Wang, Haichao
AU - Ulloa, Luis
AU - Wang, Hong
AU - Warren, H. Shaw
AU - Moldawer, Lyle L.
AU - Fink, Mitchell P.
AU - Andersson, Ulf
AU - Tracey, Kevin J.
AU - Yang, Huan
PY - 2003/1/1
Y1 - 2003/1/1
N2 - High mobility group box 1 (HMGB1), 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.
AB - High mobility group box 1 (HMGB1), 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.
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M3 - Article
C2 - 12765338
VL - 9
SP - 37
EP - 45
JO - Molecular Medicine
JF - Molecular Medicine
SN - 1076-1551
IS - 1-2
ER -