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

doi:https://doi.org/10.1007/bf03402105

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 journal › Article › peer-review

267 Scopus citations

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
DOIs	https://doi.org/10.1007/bf03402105
State	Published - 2003
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Molecular Biology
Genetics
Genetics(clinical)

Access to Document

https://doi.org/10.1007/bf03402105

Cite this

Li, J., Kokkola, R., Tabibzadeh, S., Yang, R., Ochani, M., Qiang, X., Harris, H. E., Czura, C. J., Wang, H., Ulloa, L., Wang, H., Warren, H. S., Moldawer, L. L., Fink, M. P., Andersson, U., Tracey, K. J., & Yang, H. (2003). Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Molecular Medicine, 9(1-2), 37-45. https://doi.org/10.1007/bf03402105

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.

@article{283bd6c6a8874d1d8c374f8d45db938b,

title = "Structural basis for the proinflammatory cytokine activity of high mobility group box 1",

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",

year = "2003",

doi = "https://doi.org/10.1007/bf03402105",

language = "English (US)",

volume = "9",

pages = "37--45",

journal = "Molecular medicine (Cambridge, Mass.)",

issn = "1076-1551",

publisher = "Feinstein Institute for Medical Research",

number = "1-2",

}

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, 2003, p. 37-45.

Research output: Contribution to journal › Article › peer-review

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

Y1 - 2003

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.

UR - http://www.scopus.com/inward/record.url?scp=0038276946&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0038276946&partnerID=8YFLogxK

U2 - https://doi.org/10.1007/bf03402105

DO - https://doi.org/10.1007/bf03402105

M3 - Article

C2 - 12765338

VL - 9

SP - 37

EP - 45

JO - Molecular medicine (Cambridge, Mass.)

JF - Molecular medicine (Cambridge, Mass.)

SN - 1076-1551

IS - 1-2

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this