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Structural Basis for the Proinflammatory Cytokine Activity of High Mobility Group Box 1

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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.

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Authors and Affiliations

  1. Laboratory of Biomedical Science, North Shore-Long Island Jewish Research Institute, 350 Community Drive, Manhasset, NY, 11030, USA

    Jianhua Li, Mahendar Ochani, **aoling Qiang, Christopher J. Czura, Haichao Wang, Luis Ulloa, Hong Wang, Kevin J. Tracey & Huan Yang

  2. Center for Molecular Medicine, Karolinska Hospital, 171 76, Stockholm, Sweden

    Riikka Kokkola, Helena E. Harris & Ulf Andersson

  3. Department of Obstetrics and Gynecology, Stony Brook University, Stony Brook, NY, 11794, USA

    Siamak Tabibzadeh

  4. Department of Critical Care Medicine, University of Pittsburgh Medical Center, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Runkuan Yang & Mitchell P. Fink

  5. Infectious Disease Unit, Massachusetts General Hospital, East 149 13th Street, Charlestown, MA, 02129, USA

    H. Shaw Warren

  6. Department of Surgery, University of Florida College of Medicine, Shands Hospital, 1600 SW Archer Road, Gainesville, FL, 32610, USA

    Lyle L. Moldawer

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  1. Jianhua Li
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  11. Hong Wang
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Correspondence to Huan Yang.

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Li, J., Kokkola, R., Tabibzadeh, S. et al. Structural Basis for the Proinflammatory Cytokine Activity of High Mobility Group Box 1. Mol Med 9, 37–45 (2003). https://doi.org/10.1007/BF03402105

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