Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity
| Autor: | Tetsuya Yamada, Hisanori Horiuchi, Tomohiro Kimura, Masahiro Nishibori, Takahiro Horiuchi, Keisuke Nagano, Hideki Katagiri, Takashi Hayashi, Natsumi Sakata, Keyue Liu, Yoshihiro Narumi, Ryutaro Shirakawa, Sohei Tsukita |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty endocrine system diseases medicine.medical_treatment Inflammation chemical and pharmacologic phenomena Pharmacology p38 MAPK HMGB1 Biochemistry Proinflammatory cytokine 03 medical and health sciences Mice Protein Domains In vivo Internal medicine Extracellular medicine cytokine Animals Humans HMGB1 Protein Molecular Biology Liver injury biology Chemistry digestive oral and skin physiology nutritional and metabolic diseases Molecular Bases of Disease Cell Biology medicine.disease Antibodies Neutralizing Metformin 030104 developmental biology Cytokine Endocrinology RAW 264.7 Cells biology.protein medicine.symptom medicine.drug Protein Binding liver injury |
| Zdroj: | The Journal of Biological Chemistry |
| ISSN: | 1083-351X |
| Popis: | Metformin is the first-line drug in the treatment of type 2 diabetes. In addition to its hypoglycemic effect, metformin has an anti-inflammatory function, but the precise mechanism promoting this activity remains unclear. High mobility group box 1 (HMGB1) is an alarmin that is released from necrotic cells and induces inflammatory responses by its cytokine-like activity and is, therefore, a target of anti-inflammatory therapies. Here we identified HMGB1 as a novel metformin-binding protein by affinity purification using a biotinylated metformin analogue. Metformin directly bound to the C-terminal acidic tail of HMGB1. Both in vitro and in vivo, metformin inhibited inflammatory responses induced by full-length HMGB1 but not by HMGB1 lacking the acidic tail. In an acetaminophen-induced acute liver injury model in which HMGB1 released from injured cells exacerbates the initial injury, metformin effectively reduced liver injury and had no additional inhibitory effects when the extracellular HMGB1 was blocked by anti-HMGB1-neutralizing antibody. In summary, we report for the first time that metformin suppresses inflammation by inhibiting the extracellular activity of HMGB1. Because HMGB1 plays a major role in inflammation, our results suggest possible new ways to manage HMGB1-induced inflammation. |
| Databáze: | OpenAIRE |
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