title: 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.
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.
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Park
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Moon
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Son
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Lee
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Jae-Kyeong
authors.initials: JK
authors.lastname: Byun
authors.affiliation: College of Pharmacy, Gachon University of Medicine and Science, Yeonsu-gu, Incheon, 406-799, Korea.
authors.forename: Dong Yun
authors.initials: DY
authors.lastname: Shin
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Chul-Woo
authors.initials: CW
authors.lastname: Yang
authors.affiliation: The Rheumatism Research Center, The Catholic University of Korea, Seoul, South Korea. Electronic address: iammila@catholic.ac.kr.
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010766:Phosphorylation / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D008687:Metformin; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase