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High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease.

Pisetsky DS, Erlandsson-Harris H, Andersson U - Arthritis Res. Ther. (2008)

Bottom Line: To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death.HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses.New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA. piset001@mc.duke.edu

ABSTRACT
High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 can serve as an alarmin to activate the innate system and mediate a wide range of physiological and pathological responses. To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death. HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses. As shown in studies on patients as well as animal models, HMGB1 can play an important role in the pathogenesis of rheumatic disease, including rheumatoid arthritis, systemic lupus erythematosus, and polymyositis among others. New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

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High-mobility group box protein 1 (HMGB1) expression in collagen-induced arthritis. The presence of cells expressing HMGB1 in the invading pannus of collagen-induced arthritis is shown. In this experiment, the section was stained for HMGB1 using affinity-purified polyclonal rabbit anti-HMGB1 antibodies (BD Pharmingen, San Diego, CA, USA) followed by biotin-labeled Fab2 fragments of a donkey anti-rabbit antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA). The sections then were exposed to avidin-biotin-horseradish peroxidase (Vectastain Elite, ABC kit; Vector Laboratories, Burlingame, CA, USA), and color reaction was generated with diaminobenzidine (DAB). Reproduced with permission from Nature Insight 2002, 420: 845–846 . Copyright 2002, Macmillan Publishers Ltd.
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Figure 2: High-mobility group box protein 1 (HMGB1) expression in collagen-induced arthritis. The presence of cells expressing HMGB1 in the invading pannus of collagen-induced arthritis is shown. In this experiment, the section was stained for HMGB1 using affinity-purified polyclonal rabbit anti-HMGB1 antibodies (BD Pharmingen, San Diego, CA, USA) followed by biotin-labeled Fab2 fragments of a donkey anti-rabbit antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA). The sections then were exposed to avidin-biotin-horseradish peroxidase (Vectastain Elite, ABC kit; Vector Laboratories, Burlingame, CA, USA), and color reaction was generated with diaminobenzidine (DAB). Reproduced with permission from Nature Insight 2002, 420: 845–846 . Copyright 2002, Macmillan Publishers Ltd.

Mentions: Immunohistochemical staining of synovial tissue obtained from mice and rats with collagen-induced arthritis (CIA) or adjuvant-induced arthritis indicates a significant increase in the extracellular expression of HMGB-1 and its appearance in the cytoplasm of macrophage-like cells and vascular endo-thelial cells in particular. In longitudinal studies of synovial tissue from rats with CIA, the production of HMGB1, TNF-α, and IL-β showed similar kinetics for production, without a definite sequential order [49-54]. At early time points, HMGB1 expression in this model is almost exclusively restricted to the nuclear compartment while, as disease proceeds, extranuclear HMGB1 becomes evident in resident cells in the synovium (Figure 2).


High-mobility group box protein 1 (HMGB1): an alarmin mediating the pathogenesis of rheumatic disease.

Pisetsky DS, Erlandsson-Harris H, Andersson U - Arthritis Res. Ther. (2008)

High-mobility group box protein 1 (HMGB1) expression in collagen-induced arthritis. The presence of cells expressing HMGB1 in the invading pannus of collagen-induced arthritis is shown. In this experiment, the section was stained for HMGB1 using affinity-purified polyclonal rabbit anti-HMGB1 antibodies (BD Pharmingen, San Diego, CA, USA) followed by biotin-labeled Fab2 fragments of a donkey anti-rabbit antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA). The sections then were exposed to avidin-biotin-horseradish peroxidase (Vectastain Elite, ABC kit; Vector Laboratories, Burlingame, CA, USA), and color reaction was generated with diaminobenzidine (DAB). Reproduced with permission from Nature Insight 2002, 420: 845–846 . Copyright 2002, Macmillan Publishers Ltd.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483460&req=5

Figure 2: High-mobility group box protein 1 (HMGB1) expression in collagen-induced arthritis. The presence of cells expressing HMGB1 in the invading pannus of collagen-induced arthritis is shown. In this experiment, the section was stained for HMGB1 using affinity-purified polyclonal rabbit anti-HMGB1 antibodies (BD Pharmingen, San Diego, CA, USA) followed by biotin-labeled Fab2 fragments of a donkey anti-rabbit antibody (Jackson ImmunoResearch Laboratories, Inc., West Grove, PA, USA). The sections then were exposed to avidin-biotin-horseradish peroxidase (Vectastain Elite, ABC kit; Vector Laboratories, Burlingame, CA, USA), and color reaction was generated with diaminobenzidine (DAB). Reproduced with permission from Nature Insight 2002, 420: 845–846 . Copyright 2002, Macmillan Publishers Ltd.
Mentions: Immunohistochemical staining of synovial tissue obtained from mice and rats with collagen-induced arthritis (CIA) or adjuvant-induced arthritis indicates a significant increase in the extracellular expression of HMGB-1 and its appearance in the cytoplasm of macrophage-like cells and vascular endo-thelial cells in particular. In longitudinal studies of synovial tissue from rats with CIA, the production of HMGB1, TNF-α, and IL-β showed similar kinetics for production, without a definite sequential order [49-54]. At early time points, HMGB1 expression in this model is almost exclusively restricted to the nuclear compartment while, as disease proceeds, extranuclear HMGB1 becomes evident in resident cells in the synovium (Figure 2).

Bottom Line: To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death.HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses.New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA. piset001@mc.duke.edu

ABSTRACT
High-mobility group box protein 1 (HMGB1) is a non-histone nuclear protein that has a dual function. Inside the cell, HMGB1 binds DNA, regulating transcription and determining chromosomal architecture. Outside the cell, HMGB1 can serve as an alarmin to activate the innate system and mediate a wide range of physiological and pathological responses. To function as an alarmin, HMGB1 translocates from the nucleus of the cell to the extra-cellular milieu, a process that can take place with cell activation as well as cell death. HMGB1 can interact with receptors that include RAGE (receptor for advanced glycation endproducts) as well as Toll-like receptor-2 (TLR-2) and TLR-4 and function in a synergistic fashion with other proinflammatory mediators to induce responses. As shown in studies on patients as well as animal models, HMGB1 can play an important role in the pathogenesis of rheumatic disease, including rheumatoid arthritis, systemic lupus erythematosus, and polymyositis among others. New approaches to therapy for these diseases may involve strategies to inhibit HMGB1 release from cells, its interaction with receptors, and downstream signaling.

Show MeSH
Related in: MedlinePlus