High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis.
Rille Pullerits,Ing-Marie Jonsson,Margareta Verdrengh,Maria Bokarewa,Ulf Andersson,Helena Erlandsson-Harris,Andrej Tarkowski +6 more
TLDR
The results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-kappaB activation.Abstract:
Objective
To examine the potential role of high mobility group box chromosomal protein 1 (HMGB-1) in the pathogenesis of arthritis.
Methods
Mice were injected intraarticularly with 1 μg or 5 μg of HMGB-1. Joints were dissected on days 4, 7, and 28 after injection and were evaluated histopathologically and immunohistochemically. To investigate the importance of different white blood cell populations for the development of arthritis, in vivo cell depletion procedures were performed. In addition, spleen cells were cultured in the presence of HMGB-1, and nuclear factor κB (NF-κB) activation was detected by electrophoretic mobility shift assay.
Results
Injection of recombinant HMGB-1 (rHMGB-1) into different mouse strains resulted in an overall frequency of arthritis in 80% of the animals. The inflammation was characterized by mild to moderate synovitis and lasted for at least 28 days. The majority of cells found in the inflamed synovium were Mac-1+ macrophages, whereas only a few CD4+ lymphocytes were detected. Pannus formation was observed in some cases 7 and 28 days after HMGB-1 injection. No significant differences were found with respect to incidence and severity of arthritis between mice depleted of monocytes, granulocytes, or lacking T/B lymphocytes. However, combined removal of monocytes and neutrophils resulted in a 43% lower incidence of arthritis. Mice rendered deficient in the interleukin-1 (IL-1) receptor did not develop inflammation upon challenge with HMGB-1. In vitro data corroborate this finding, showing that rHMGB-1 activated NF-κB, a major pathway leading to IL-1 production.
Conclusion
Our results indicate that HMGB-1 is not a mere expression of inflammatory responses, but on its own, it triggers joint inflammation by activating macrophages and inducing production of IL-1 via NF-κB activation.read more
Citations
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Journal ArticleDOI
HMGB1 Is a Therapeutic Target for Sterile Inflammation and Infection
Ulf Andersson,Kevin J. Tracey +1 more
TL;DR: Experimental strategies that selectively target HMGB1 and TLR4 effectively reverse and prevent activation of innate immunity and significantly attenuate damage in diverse models of sterile and infection-induced threat.
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Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion
Tiziana Bonaldi,Fabio Talamo,Paola Scaffidi,Denise Ferrera,Annalisa Porto,Angela Bachi,Anna Rubartelli,Alessandra Agresti,Marco Bianchi +8 more
TL;DR: It is shown here that in all cells HMGB1 shuttles actively between the nucleus and cytoplasm, and secreted when monocytic cells receive an appropriate second signal.
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Resistin, an adipokine with potent proinflammatory properties
TL;DR: The results indicate that resistin is a new and important member of the cytokine family with potent regulatory functions and makes it a novel and interesting therapeutic target in chronic inflammatory diseases such as rheumatoid arthritis.
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DAMPening Inflammation by Modulating TLR Signalling
Anna M. Piccinini,Kim S. Midwood +1 more
TL;DR: The current knowledge about distinct signalling cascades resulting from self TLR activation is explored and the involvement of endogenous TLR activators in disease is discussed to highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.
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Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation
Ravichandran Ramasamy,Susan J. Vannucci,Shirley ShiDu Yan,Kevan C. Herold,Shi Fang Yan,Ann Marie Schmidt +5 more
TL;DR: It is hypothesized that AGEs cause perturbation in a diverse group of diseases, such as diabetes, inflammation, neurodegeneration, and aging, and it is proposed that targeting this pathway may represent a logical step in the prevention/treatment of the sequelae of these disorders.
References
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Book
Cellular and Molecular Immunology
TL;DR: Cellular and molecular immunology , Cellular and molecular Immunology , کتابخانه الکرونیک و دیجیتال - آذرسا
Journal ArticleDOI
HMG-1 as a Late Mediator of Endotoxin Lethality in Mice
Haichao Wang,Ona Bloom,Minghuang Zhang,Jaideep M. Vishnubhakat,Michael Ombrellino,Jiantu Che,Asia Frazier,Huan Yang,Svetlana Ivanova,Lyudmila V. Borovikova,Kirk R. Manogue,Eugen Faist,Edward Abraham,Jan Andersson,Ulf Andersson,Patricia E. Molina,Naji N. Abumrad,Andrew E. Sama,Kevin J. Tracey +18 more
TL;DR: High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1, and showed increased serum levels after endotoxin exposure, suggesting that this protein warrants investigation as a therapeutic target.
Journal ArticleDOI
High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes.
Ulf Andersson,Haichao Wang,Karin Palmblad,Ann-Charlotte Aveberger,Ona Bloom,Helena Erlandsson-Harris,Alfred Janson,R. Kokkola,Minghuang Zhang,Huan Yang,Kevin J. Tracey +10 more
TL;DR: Results indicate that, like other cytokine mediators of endotoxin lethality (e.g., TNF and IL-1), extracellular HMG-1 is a regulator of monocyte proinflammatory cytokine synthesis.
Journal ArticleDOI
Blockade of RAGE–amphoterin signalling suppresses tumour growth and metastases
Akihiko Taguchi,Blood Dc,del Toro G,Canet A,Lee Dc,Wu Qu,Nozomu Tanji,Yi-Fan Lu,Evanthia Lalla,Caifeng Fu,Marion A. Hofmann,Thomas Kislinger,Ingram M,Lu A,Hirokazu Tanaka,Osamu Hori,Satoshi Ogawa,David M. Stern,Ann Marie Schmidt +18 more
TL;DR: In this article, the authors demonstrate that inhibition of RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.
Journal ArticleDOI
The Receptor for Advanced Glycation End Products (RAGE) Is a Cellular Binding Site for Amphoterin MEDIATION OF NEURITE OUTGROWTH AND CO-EXPRESSION OF RAGE AND AMPHOTERIN IN THE DEVELOPING NERVOUS SYSTEM
Osamu Hori,Jerold Brett,Timothy Slattery,Rong Cao,Jinghua Zhang,Jing Xian Chen,Mariko Nagashima,Erik R. Lundh,Sharmila Vijay,Di Nitecki,John Morser,David M. Stern,Ann Marie Schmidt +12 more
TL;DR: The receptor for advanced glycation end products (RAGE), a newly-identified member of the immunoglobulin superfamily, mediates interactions of AGE-modified proteins with endothelium and other cell types.
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