Clarification of the roles of PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) is indispensable for therapeutic strategies against various inflammatory diseases. RAGE (receptor for advanced glycation end-products) is one of the PRRs (pattern recognition receptors) and has been implicated in autoimmune and inflammatory diseases. Effective remedies targeting RAGE are required for the diseases. In the present study, we show that cAMP-induced modulation of the RAGE isoform in macrophages can control the inflammatory state in both in vitro and in vivo experimental conditions. The RAGE ligand S100B stimulated MCP-1 (monocyte chemoattractant protein-1) secretion from peritoneal macrophages, but cAMP elevation suppressed it by converting the RAGE isoform from a membrane-bound into a soluble form. This shedding is the result of ectodomain cleavage of mRAGE (membrane-bound RAGE) by MMP9 (matrix metalloproteinase 9). Furthermore, forskolin significantly inhibited peritoneal macrophage accumulation in a mouse S100B-induced peritonitis model. These results suggest that cAMP serves as a negative regulator of ligand–RAGE signalling and macrophage recruitment by mRAGE down-regulation and formation of decoys as soluble receptors. The present study should deepen our understanding of the pathogenesis of RAGE-mediated tissue derangement and provide new clues for overcoming RAGE-related inflammatory diseases.
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October 2014
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Research Article|
September 08 2014
cAMP ameliorates inflammation by modulation of macrophage receptor for advanced glycation end-products
So Motoyoshi;
So Motoyoshi
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Yasuhiko Yamamoto;
Yasuhiko Yamamoto
1
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
1To whom correspondence should be addressed (email [email protected]).
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Seiichi Munesue;
Seiichi Munesue
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Hirobumi Igawa;
Hirobumi Igawa
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Ai Harashima;
Ai Harashima
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Hidehito Saito;
Hidehito Saito
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Dong Han;
Dong Han
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Takuo Watanabe;
Takuo Watanabe
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Hiroshi Sato;
Hiroshi Sato
†Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, 920-1192, Japan
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Hiroshi Yamamoto
Hiroshi Yamamoto
*Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, 920-8640, Japan
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Publisher: Portland Press Ltd
Received:
January 22 2014
Revision Received:
June 30 2014
Accepted:
July 04 2014
Accepted Manuscript online:
July 04 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2014 Biochemical Society
2014
Biochem J (2014) 463 (1): 75–82.
Article history
Received:
January 22 2014
Revision Received:
June 30 2014
Accepted:
July 04 2014
Accepted Manuscript online:
July 04 2014
Citation
So Motoyoshi, Yasuhiko Yamamoto, Seiichi Munesue, Hirobumi Igawa, Ai Harashima, Hidehito Saito, Dong Han, Takuo Watanabe, Hiroshi Sato, Hiroshi Yamamoto; cAMP ameliorates inflammation by modulation of macrophage receptor for advanced glycation end-products. Biochem J 1 October 2014; 463 (1): 75–82. doi: https://doi.org/10.1042/BJ20140084
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