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.

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.

• Authors: Keisuke Maeshima, Kunihiro Yamaoka, Satoshi Kubo, Kazuhisa Nakano, Shigeru Iwata, Kazuyoshi Saito, Masanobu Ohishi, Hisaaki Miyahara, Shinya Tanaka, Koji Ishii, Hironobu Yoshimatsu, Yoshiya Tanaka
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 64 Issue 6 Pg. 1790-8 (Jun 2012) ISSN: 1529-0131 [Electronic] United States
• PMID: 22147632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 by the American College of Rheumatology.

Chemical References

• Interleukin-17
• Piperidines
• Pyrimidines
• Pyrroles
• Interferon-gamma
• tofacitinib
• Janus Kinase 3

Topics

• Animals
• CD4-Positive T-Lymphocytes (drug effects, immunology, metabolism)
• Cartilage, Articular (drug effects, immunology, metabolism)
• Cell Proliferation (drug effects)
• Humans
• Interferon-gamma (biosynthesis)
• Interleukin-17 (biosynthesis)
• Janus Kinase 3 (antagonists & inhibitors)
• Mice
• Monocytes (drug effects, immunology, metabolism)
• Piperidines
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Synovial Membrane (drug effects, immunology, metabolism)
• Synovitis (immunology, metabolism)