Structural basis for the proinflammatory cytokine activity of high mobility group box 1

Jianhua Li, Riikka Kokkola, Siamak Tabibzadeh, Runkuan Yang, Mahendar Ochani, Xiaoling Qiang, Helena E. Harris, Christopher J. Czura, Haichao Wang, Luis Ulloa, Hong Wang, H. Shaw Warren, Lyle L. Moldawer, Mitchell P. Fink, Ulf Andersson, Kevin J. Tracey, Huan Yang

Research output: Contribution to journalArticle

244 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)37-45
Number of pages9
JournalMolecular Medicine
Volume9
Issue number1-2
StatePublished - Jan 1 2003
Externally publishedYes

Fingerprint

Endotoxemia
HMG-Box Domains
Cytokines
Tumor Necrosis Factor-alpha
Macrophages
Amino Acids
Passive Immunization
Acute Lung Injury
DNA
DNA-Binding Proteins
Anorexia
Sepsis
Necrosis
Antibodies
Therapeutics

All Science Journal Classification (ASJC) codes

  • Genetics(clinical)
  • Genetics
  • Molecular Medicine
  • Molecular Biology

Cite this

Li, J., Kokkola, R., Tabibzadeh, S., Yang, R., Ochani, M., Qiang, X., ... Yang, H. (2003). Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Molecular Medicine, 9(1-2), 37-45.
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. / Structural basis for the proinflammatory cytokine activity of high mobility group box 1. In: Molecular Medicine. 2003 ; Vol. 9, No. 1-2. pp. 37-45.
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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.",
author = "Jianhua Li and Riikka Kokkola and Siamak Tabibzadeh and Runkuan Yang and Mahendar Ochani and Xiaoling Qiang and Harris, {Helena E.} and Czura, {Christopher J.} and Haichao Wang and Luis Ulloa and Hong Wang and Warren, {H. Shaw} and Moldawer, {Lyle L.} and Fink, {Mitchell P.} and Ulf Andersson and Tracey, {Kevin J.} and Huan Yang",
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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 & Yang, H 2003, 'Structural basis for the proinflammatory cytokine activity of high mobility group box 1', Molecular Medicine, vol. 9, no. 1-2, pp. 37-45.

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 journalArticle

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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JF - Molecular Medicine

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Li J, Kokkola R, Tabibzadeh S, Yang R, Ochani M, Qiang X et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Molecular Medicine. 2003 Jan 1;9(1-2):37-45.