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

被引:304
作者
Li, JH
Kokkola, R
Tabibzadeh, S
Yang, RK
Ochani, M
Qiang, XL
Harris, HE
Czura, CJ
Wang, HC
Ulloa, L
Wang, H
Warren, HS
Moldawer, LL
Fink, MP
Andersson, U
Tracey, KJ
Yang, H
机构
[1] N Shore Long Isl Jewish Res Inst, Lab Biomed Sci, Manhasset, NY 11030 USA
[2] Karolinska Inst, Ctr Mol Med, S-17176 Stockholm, Sweden
[3] SUNY Stony Brook, Dept Obstet & Gynecol, Stony Brook, NY 11794 USA
[4] Univ Pittsburgh, Med Ctr, Dept Crit Care Med, Pittsburgh, PA 15261 USA
[5] Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA
[6] Univ Florida, Coll Med, Dept Surg, Shands Hosp, Gainesville, FL 32610 USA
关键词
D O I
10.1007/BF03402105
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:37 / 45
页数:9
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