Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation

被引:56
作者
Di Fusco, Davide [1 ]
Dinallo, Vincenzo [1 ]
Monteleone, Ivan [2 ]
Laudisi, Federica [1 ]
Marafini, Irene [1 ]
Franze, Eleonora [1 ]
Di Grazia, Antonio [1 ]
Dwairi, Rami [1 ,3 ]
Colantoni, Alfredo [1 ]
Ortenzi, Angela [1 ]
Stolfi, Carmine [1 ]
Monteleone, Giovanni [1 ]
机构
[1] Univ Tor Vergata, Dept Syst Med, Rome, Italy
[2] Univ Tor Vergata, Dept Biomed & Prevent, Rome, Italy
[3] Mutah Univ, Dept Internal Med, Al Karak, Jordan
关键词
PROTEIN-KINASE; BOWEL-DISEASE; PROINFLAMMATORY RESPONSES; GASTROINTESTINAL-TRACT; EXPERIMENTAL COLITIS; CROHNS-DISEASE; CELLS; MICE; DIFFERENTIATION; EXPRESSION;
D O I
10.1042/CS20180167
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Metformin, a hypoglycemic drug used for treatment of type 2 diabetes, regulates inflammatory pathways. By using several models of intestinal inflammation, we examined whether metformin exerts anti-inflammatory effects and investigated the basic mechanism by which metformin blocks pathologic signals. Colitic mice given metformin exhibited less colonic inflammation and increased expression of active AMP-activated protein kinase, a mediator of the metabolic effects of metformin, in both epithelial and lamina propria compartments. Pharmacological inhibition of AMP-activated protein kinase reduced but did not prevent metformin-induced therapeutic effect as well as treatment of colitic mice with a pharmacological activator of AMP-activated protein kinase attenuated but did not resolve colitis. These data suggest that the anti-inflammatory effect of metformin relies on the control of additional pathways other than AMP-activated protein kinase. Indeed, metformin down-regulated p38 MAP kinase activation in colitic mice through an AMP-activated protein kinase-independent mechanism. Expression of active form of AMP-activated protein kinase was reduced in inflammatory bowel disease patients and treatment of mucosal cells of such patients with metformin enhanced AMP-activated protein kinase activation and reduced p38 MAP kinase activation, thereby inhibiting interleukin-6 expression. Our findings indicate that metformin is a good candidate for inhibiting pathological inflammation in the gut.
引用
收藏
页码:1155 / 1168
页数:14
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