title: The JAK inhibitor, tofacitinib, reduces the T cell stimulatory capacity of human monocyte-derived dendritic cells.
abstract: OBJECTIVE
  Tofacitinib, which is a Janus kinase (JAK) inhibitor, has shown clinical effects in the treatment of rheumatoid arthritis. JAKs are important kinases in lymphocyte differentiation; however, their function in dendritic cells (DCs) is unknown. In this study, the function of JAKs in DCs was investigated with tofacitinib.
  
  
  METHODS
  The effects of tofacitinib on the maturation of human monocyte-derived DCs induced by lipopolysaccharide (LPS) stimulation were investigated. In addition, its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA-positive T cells.
  
  
  RESULTS
  Tofacitinib decreased expression of CD80/CD86 in a concentration-dependent manner in LPS-stimulated DCs; however, it did not affect HLA-DR expression. Tofacitinib suppressed tumour necrosis factor, interleukin (IL)-6 and IL-1β production without affecting transforming growth factor (TGF)-β and IL-10 production. Meanwhile, CD80/CD86 expression in DCs was enhanced by type I interferon (IFN) stimulation, and the LPS-induced CD80/CD86 expression was inhibited by an antibody to type I IFN receptor. Furthermore, tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor (IRF)-7, which is a transcription factor involved in CD80/CD86 and type I IFN expression. Tofacitinib also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2,3-dioxygenase (IDO)-1 and IDO-2.
  
  
  CONCLUSIONS
  Tofacitinib, a JAK1/JAK3 inhibitor, affected the activities of human DCs. It decreased CD80/CD86 expression and T cell stimulatory capability through suppression of type I IFN signalling. These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs.
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubo
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Kondo
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamagata
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iwata
authors.affiliation: The First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D018122:B7-1 Antigen / Q000187:drug effects / Q000276:immunology; D051940:B7-2 Antigen / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D053583:Interleukin-1beta / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D010880:Piperidines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; C497964:CD86 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; C479163:tofacitinib; D053616:Janus Kinase 3
keywords: Cytokines; DMARDs (synthetic); Pharmacokinetics; Rheumatoid Arthritis; Systemic Lupus Erythematosus