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.
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Double immunofluorescence staining for mindin (red) and CD68 (green) in atherosclerotic plaques of HFD-treated APOE-/- mice. In Issue 11 of Clinical Science, Zhu et al. discuss mindin deficiency as a novel mediator in protecting against foam cell formation and atherosclerosis, through direct interaction with LXR-β; for details, see pages 1199–1213.
Research Article|
June 09 2018
Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation
Davide Di Fusco;
Davide Di Fusco
*
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Vincenzo Dinallo;
Vincenzo Dinallo
*
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Ivan Monteleone;
Ivan Monteleone
2Department of Biomedicine and Prevention, University of “Tor Vergata”, Rome, Italy
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Federica Laudisi;
Federica Laudisi
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Irene Marafini;
Irene Marafini
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Eleonora Franzè;
Eleonora Franzè
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Antonio Di Grazia;
Antonio Di Grazia
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Rami Dwairi;
Rami Dwairi
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
3Department of Internal Medicine, Mutah University, Karak, Jordan
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Alfredo Colantoni;
Alfredo Colantoni
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Angela Ortenzi;
Angela Ortenzi
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Carmine Stolfi;
Carmine Stolfi
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
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Giovanni Monteleone
1Department of Systems Medicine, University of “Tor Vergata”, Rome, Italy
Correspondence: Giovanni Monteleone ([email protected])
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Publisher: Portland Press Ltd
Received:
February 19 2018
Revision Received:
March 13 2018
Accepted:
March 14 2018
Accepted Manuscript online:
March 14 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (11): 1155–1168.
Article history
Received:
February 19 2018
Revision Received:
March 13 2018
Accepted:
March 14 2018
Accepted Manuscript online:
March 14 2018
Citation
Davide Di Fusco, Vincenzo Dinallo, Ivan Monteleone, Federica Laudisi, Irene Marafini, Eleonora Franzè, Antonio Di Grazia, Rami Dwairi, Alfredo Colantoni, Angela Ortenzi, Carmine Stolfi, Giovanni Monteleone; Metformin inhibits inflammatory signals in the gut by controlling AMPK and p38 MAP kinase activation. Clin Sci (Lond) 14 June 2018; 132 (11): 1155–1168. doi: https://doi.org/10.1042/CS20180167
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