title: The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells.
abstract: OBJECTIVE
  Tofacitinib (CP-690,550) is a novel JAK inhibitor that is currently in clinical trials for the treatment of rheumatoid arthritis (RA). The aim of this study was to examine the effects of tofacitinib in vitro and in vivo in RA, in order to elucidate the role of JAK in the disease process.
  
  
  METHODS
  CD4+ T cells, CD14+ monocytes, and synovial fibroblasts (SFs) were purified from the synovium and peripheral blood of patients with RA and were evaluated for the effect of tofacitinib on cytokine production and cell proliferation. For in vivo analysis, synovium and cartilage samples obtained from patients with RA were implanted in immunodeficient mice (SCID-HuRAg mice), and tofacitinib was administered via an osmotic minipump.
  
  
  RESULTS
  Tofacitinib treatment of CD4+ T cells originating from synovium and peripheral blood inhibited the production of interleukin-17 (IL-17) and interferon-γ (IFNγ) in a dose-dependent manner, affecting both proliferation and transcription, but had no effect on IL-6 and IL-8 production. Tofacitinib did not affect IL-6 and IL-8 production by RASFs and CD14+ monocytes. However, conditioned medium from CD4+ T cells cultured with tofacitinib inhibited IL-6 production by RASFs and IL-8 production by CD14+ monocytes. Treatment of SCID-HuRAg mice with tofacitinib decreased serum levels of human IL-6 and IL-8 and markedly suppressed invasion of synovial tissue into cartilage.
  
  
  CONCLUSIONS
  Tofacitinib directly suppressed the production of IL-17 and IFNγ and the proliferation of CD4+ T cells, resulting in inhibition of IL-6 production by RASFs and IL-8 production by CD14+ cells and decreased cartilage destruction. In CD4+ T cells, presumably Th1 and Th17 cells, JAK plays a crucial role in RA synovitis.
authors.affiliation: University of Occupational and Environmental Health, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Maeshima
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kubo
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nakano
authors.forename: Shigeru
authors.initials: S
authors.lastname: Iwata
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Masanobu
authors.initials: M
authors.lastname: Ohishi
authors.forename: Hisaaki
authors.initials: H
authors.lastname: Miyahara
authors.forename: Shinya
authors.initials: S
authors.lastname: Tanaka
authors.forename: Koji
authors.initials: K
authors.lastname: Ishii
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yoshimatsu
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Tanaka
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002358:Cartilage, Articular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D020381:Interleukin-17 / Q000096:biosynthesis*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010880:Piperidines; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D013585:Synovitis / Q000276:immunology / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D007371:Interferon-gamma; C479163:tofacitinib; D053616:Janus Kinase 3