Open AccessThe JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon‐γ and interleukin‐17 production by human CD4+ T cells
Author(s) -
Maeshima Keisuke,
Yamaoka Kunihiro,
Kubo Satoshi,
Nakano Kazuhisa,
Iwata Shigeru,
Saito Kazuyoshi,
Ohishi Masanobu,
Miyahara Hisaaki,
Tanaka Shinya,
Ishii Koji,
Yoshimatsu Hironobu,
Tanaka Yoshiya
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34329
Subject(s) - tofacitinib , medicine , synovitis , cytokine , cd14 , immunology , rheumatoid arthritis , interleukin , in vivo , cancer research , biology , immune system , microbiology and biotechnology
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. Conclusion 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.