title: Metformin downregulates Th17 cells differentiation and attenuates murine autoimmune arthritis.
abstract: BACKGROUND
  This study was undertaken to determine whether metformin has anti-inflammatory effects in the collagen antibody-induced arthritis (CAIA) murine model. The effect of metformin on Th17 cell differentiation was also investigated.
  
  
  METHODS
  CAIA mice were treated with 100 and 150 mg/kg i.p. metformin (low- and high-dose groups, respectively). Arthritis activity and histological joint destruction were studied. Flow cytometry was used to (i) determine RORγt-expressing CD4+ percentages in draining axillary lymph nodes (ALNs) from metformin-treated and untreated mice with CAIA, (ii) determine Th17 percentages in splenic CD4+ T cells cultured ex vivo for 3 days in Th17-differentiation-inducing conditions, and (iii) determine the percentages of RORγt+CD4+ T cells when normal splenic T cells from DBA/1 mice were cultured in Th17-differentiation-inducing conditions together with various metformin doses. Western blot analysis was used to assess the intracellular signaling of the metformin-treated splenocytes.
  
  
  RESULTS
  Metformin attenuated both arthritis scores and bone destruction in CAIA mice, decreased the serum levels of the pro-inflammatory cytokines, TNF-α and IL-1, and reduced the number of RORγt+CD4+ T cells in the ALNs. Splenocytes from metformin-treated CAIA mice differentiated less readily into Th17 cells upon ex vivo stimulation. Metformin treatment of normal cells cultured in Th17-differentiation-inducing conditions decreased the number of RORγt-expressing CD4+ cells in a dose-dependent manner and downregulated STAT3 phosphorylation via the AMPK pathway.
  
  
  CONCLUSIONS
  Metformin had an anti-inflammatory effect on murine autoimmune arthritis due to the inhibition of Th17 cell differentiation. Metformin may have a possible therapeutic value for treatment of rheumatoid arthritis.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Kwi Young
authors.initials: KY
authors.lastname: Kang
authors.forename: Young-Kyun
authors.initials: YK
authors.lastname: Kim
authors.forename: Hyoju
authors.initials: H
authors.lastname: Yi
authors.forename: Juryun
authors.initials: J
authors.lastname: Kim
authors.forename: Hae-Rin
authors.initials: HR
authors.lastname: Jung
authors.forename: In Je
authors.initials: IJ
authors.lastname: Kim
authors.forename: Jae-Hyoung
authors.initials: JH
authors.lastname: Cho
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008811:Mice, Inbred DBA; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D013154:Spleen / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D008687:Metformin