| RRC ID |
65055
|
| 著者 |
Horiuchi T, Sakata N, Narumi Y, Kimura T, Hayashi T, Nagano K, Liu K, Nishibori M, Tsukita S, Yamada T, Katagiri H, Shirakawa R, Horiuchi H.
|
| タイトル |
Metformin directly binds the alarmin HMGB1 and inhibits its proinflammatory activity.
|
| ジャーナル |
J Biol Chem
|
| Abstract |
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.
|
| 巻・号 |
292(20)
|
| ページ |
8436-8446
|
| 公開日 |
2017-5-19
|
| DOI |
10.1074/jbc.M116.769380
|
| PII |
S0021-9258(20)39422-9
|
| PMID |
28373282
|
| PMC |
PMC5437248
|
| MeSH |
Animals
Antibodies, Neutralizing / chemistry
Antibodies, Neutralizing / pharmacology
HMGB1 Protein / antagonists & inhibitors*
HMGB1 Protein / metabolism*
Humans
Inflammation / drug therapy
Inflammation / metabolism
Metformin / pharmacokinetics*
Metformin / pharmacology
Mice
Protein Binding
Protein Domains
RAW 264.7 Cells
|
| IF |
4.238
|
| リソース情報 |
| ヒト・動物細胞 |
RAW 264(RCB0535) |
