title: Dichloroacetate induces regulatory T-cell differentiation and suppresses Th17-cell differentiation by pyruvate dehydrogenase kinase-independent mechanism.
abstract: OBJECTIVE
  Recently, there has been a growing interest in the mechanism of action of dichloroacetate (DCA) for T-cell differentiation; however, this mechanism has not been elucidated in detail. Therefore, this study aimed to investigate the mechanism of action of DCA for Treg and Th17 differentiation with pyruvate dehydrogenase kinase (PDHK) inhibitor (AZD7545) and PDHK knockdown.
  
  
  METHODS
  Inhibitory activity of DCA and AZD7545 against recombinant PDHK and intracellular PDH phosphorylation was measured. The effects of DCA and AZD7545 on T-cell differentiation were assessed by analysing Foxp3+T-cell populations for Treg differentiation and IL-17A production for Th17 differentiation. For reactive oxygen species (ROS) production, DCFDA was used as an indicator.
  
  
  RESULTS
  Dichloroacetate and AZD7545 inhibited PDHK activity of recombinant PDHK and intracellular PDH phosphorylation. DCA was capable of inducing Treg differentiation and suppressing Th17 differentiation. The effects of DCA were independent of PDHK because neither AZD7545 nor knockdown of PDHK1 or PDHK3 affected T-cell differentiation. DCA was determined to be capable of inducing ROS production, and the effects of DCA on T-cell differentiation were shown to be dependent on ROS production.
  
  
  CONCLUSIONS
  Dichloroacetate possesses Treg induction and Th17 suppression, which is independent of PDHK and dependent on ROS production.
authors.affiliation: Group III Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Makita
authors.affiliation: Group III Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Ishiguro
authors.affiliation: Group III Pain & Neuroscience Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Group III Biologics & Immuno-Oncology Laboratories, Daiichi Sankyo Co. Ltd., Tokyo, Japan.
authors.forename: Futoshi
authors.initials: F
authors.lastname: Nara
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D058504:Th17 Cells / Q000502:physiology*
chemical_list: C523124:AZD 7545; D000813:Anilides; D004791:Enzyme Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases
keywords: Th17; Treg; dichloroacetate; pyruvate dehydrogenase kinase; reactive oxygen species