Dr. Y. Tanaka has received consulting fees, speaking fees, and/or honoraria from Eisai, Pfizer, Abbott, Janssen Pharma, Takeda, AstraZeneca, Astellas, Asahi Kasei Pharma, and GlaxoSmithKline (less than $10,000 each) and from Chugai and Mitsubishi Tanabe Pharma (more than $10,000 each).
The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells
Article first published online: 25 MAY 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 6, pages 1790–1798, June 2012
How to Cite
Maeshima, K., Yamaoka, K., Kubo, S., Nakano, K., Iwata, S., Saito, K., Ohishi, M., Miyahara, H., Tanaka, S., Ishii, K., Yoshimatsu, H. and Tanaka, Y. (2012), The JAK inhibitor tofacitinib regulates synovitis through inhibition of interferon-γ and interleukin-17 production by human CD4+ T cells. Arthritis & Rheumatism, 64: 1790–1798. doi: 10.1002/art.34329
- Issue published online: 25 MAY 2012
- Article first published online: 25 MAY 2012
- Accepted manuscript online: 6 DEC 2011 04:04PM EST
- Manuscript Accepted: 1 DEC 2011
- Manuscript Received: 28 APR 2011
- Ministry of Health, Labor, and Welfare of Japan (Research Grant-In-Aid for Scientific Research)
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- University of Occupational and Environmental Health, Japan
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.