Maeshima Keisuke, Yamaoka Kunihiro, Kubo Satoshi, Nakano Kazuhisa, Iwata Shigeru, Saito Kazuyoshi, Ohishi Masanobu, Miyahara Hisaaki, Tanaka Shinya, Ishii Koji, Yoshimatsu Hironobu, Tanaka Yoshiya
University of Occupational and Environmental Health, Japan.
Arthritis Rheum. 2012 Jun;64(6):1790-8. doi: 10.1002/art.34329. Epub 2011 Dec 6.
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.
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.
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.
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.
托法替布（CP - 690,550）是一种新型的JAK抑制剂，目前正处于治疗类风湿关节炎（RA）的临床试验阶段。本研究旨在探讨托法替布在体外和体内对RA的影响，以阐明JAK在疾病进程中的作用。
从RA患者的滑膜和外周血中纯化出CD4 + T细胞、CD14 + 单核细胞和滑膜成纤维细胞（SFs），并评估托法替布对细胞因子产生和细胞增殖的影响。对于体内分析，将从RA患者获得的滑膜和软骨样本植入免疫缺陷小鼠（SCID - HuRAg小鼠），并通过渗透微型泵给予托法替布。
托法替布处理来自滑膜和外周血的CD4 + T细胞以剂量依赖方式抑制白细胞介素 - 17（IL - 17）和干扰素 - γ（IFNγ）的产生，影响增殖和转录，但对IL - 6和IL - 8的产生没有影响。托法替布不影响RA滑膜成纤维细胞（RASFs）和CD14 + 单核细胞产生IL - 6和IL - 8。然而，用托法替布培养的CD4 + T细胞的条件培养基抑制RASFs产生IL - 6和CD14 + 单核细胞产生IL - 8。用托法替布治疗SCID - HuRAg小鼠可降低人IL - 6和IL - 8的血清水平，并显著抑制滑膜组织向软骨的侵袭。
托法替布直接抑制IL - 17和IFNγ的产生以及CD4 + T细胞的增殖，导致RASFs产生IL - 6和CD14 + 细胞产生IL - 8受到抑制，并减少软骨破坏。在CD4 + T细胞（可能是Th1和Th17细胞）中，JAK在RA滑膜炎中起关键作用。
