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Transl Res. 2016 Jul;173:115-130. doi: 10.1016/j.trsl.2016.03.006. Epub 2016 Mar 22.

Metformin attenuates graft-versus-host disease via restricting mammalian target of rapamycin/signal transducer and activator of transcription 3 and promoting adenosine monophosphate-activated protein kinase-autophagy for the balance between T helper 17 and Tregs.

Author information

1
The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
2
Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
3
College of Pharmacy, Gachon University of Medicine and Science, Yeonsu-gu, Incheon, 406-799, Korea.
4
Transplant Research Center, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea. Electronic address: yangch@catholic.ac.kr.
5
The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea. Electronic address: iammila@catholic.ac.kr.

Abstract

Acute graft-versus-host disease (aGVHD), caused by donor T cell-mediated injury to host tissues, is a problem in allogeneic bone marrow transplantation. The transition from naïve to effector T cells is accompanied by shift in metabolism main pathway; from glucose oxidative phosphorylation to aerobic glycolysis. Adenosine monophosphate-activated protein kinase (AMPK) is a serine/threonine kinase that is a metabolic sensor that helps maintain cellular energy homeostasis. Although AMPK activation can exert anti-inflammatory properties by negatively regulating pro-inflammatory mediators, its role as a therapeutic potential of graft-versus-host disease development remains unclear. In this study, we found that the intraperitoneal administration of metformin, which activates AMPK signaling significantly, ameliorated the clinical severity of aGHVD and lethality. This was associated with reductions in type I T helper (Th1) and Th17 and rises in Th2 and regulatory T (Treg) cell. The enhanced signal transducer and activator of transcription 3 activation noted during the development of aGVHD was reduced by metformin treatment. Furthermore, metformin-treated Th17 cells became converted into Treg cells via enhanced autophagy. The reduction in mortality associated with metformin treatment was associated with inhibition of the mammalian target of rapamycin/signal transducer and activator of transcription 3 pathway. These results suggest that metformin might be of significant use in the treatment of patients with aGVHD.

PMID:
27126953
DOI:
10.1016/j.trsl.2016.03.006
[Indexed for MEDLINE]

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