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

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• 作者：Min-Jung Park^a ; ¹ ; Seon-Yeong Lee^a ; ¹ ; Su-Jin Moon^b ; ¹ ; Hye-Jin Son^a ; Sung-Hee Lee^a ; Eun-Kyung Kim^a ; Jae-Kyeong Byun^a ; Dong Yun Shin^c ; Sung-Hwan Park^a ; Chul-Woo Yang^d ; ² ; ^{yangch@catholic.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Mi-La Cho^a ; ² ; ^{iammila@catholic.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：aGVHD ; acute graft-versus-host disease ; BMT ; bone marrow transplantation ; AMPK ; Adenosine monophosphate&ndash ; activated protein kinase ; Treg ; regulatory T ; Th ; T helper cell ; STAT3 ; signal transducer and activator of transcription ; mTOR ; mammalian target of rapamycin
• 刊名：Translational Research
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：173
• 期：Complete
• 页码：115-130
• 全文大小：4485 K

文摘

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.