JAK inhibitor has the amelioration effect in lupus-prone mice: the involvement of IFN signature gene downregulation

Keigo Ikeda,Hiroshi Tsushima,Maki Fujishiro,Hideoki Ogawa,Mikiko Kawasaki,Tomoko Miyashita,Satoshi Suzuki,Kunihiro Hayakawa,Naoto Tamura,Shinji Morimoto,Iwao Sekigawa,Takuya Hirai,Kenji Takamori

doi:10.1186/s12865-017-0225-9

Keigo Ikeda, Hiroshi Tsushima + Show 11 more

Open Access

https://doi.org/10.1186/s12865-017-0225-9

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Abstract

BackgroundWe previously reported that JAK–STAT-pathway mediated regulation of IFN-regulatory factor genes could play an important role in SLE pathogenesis. Here, we evaluated the efficacy of the JAK inhibitor tofacitinib (TOFA) for controlling IFN signalling via the JAK–STAT pathway and as a therapeutic for SLE.ResultsWe treated NZB/NZW F1 mice with TOFA and assessed alterations in their disease, pathological, and immunological conditions. Gene-expression results obtained from CD4+ T cells (SLE mice) and CD3+ T cells (human SLE patients) were measured by DNA microarray and qRT-PCR. TOFA treatment resulted in reduced levels of anti-dsDNA antibodies, decreased proteinuria, and amelioration of nephritis as compared with those observed in control animals. Moreover, we observed the rebalance in the populations of naïve CD4+ T cells and effector/memory cells in TOFA-treated mice; however, treatment with a combination of TOFA and dexamethasone (DEXA) elicited a stronger inhibitory effect toward the effector/memory cells than did TOFA or DEXA monotherapy. We also detected decreased expression of several IFN-signature genes Ifit3 and Isg15 in CD4+ from SLE-prone mice following TOFA and DEXA treatment, and IFIT3 in CD3+ T cells from human patients following immunosuppressant therapy including steroid, respectively.ConclusionModulation of type I IFN signalling via JAK–STAT inhibition may exert a beneficial effect in SLE patients, and our results suggest that TOFA could be utilised for the development of new SLE-specific therapeutic strategies.

Highlights

We previously reported that Janus kinase (JAK)–signal transducers and activator of transcription (STAT)-pathway mediated regulation of IFN-regulatory factor genes could play an important role in systemic lupus erythematosus (SLE) pathogenesis
Our findings suggested that JAK–STAT-pathway mediated regulation of IFN-regulatory factor (IRF)-related genes might contribute to SLE pathogenesis and disease activity [8]
TOFA treatment suppressed IFN-induced gene Ifit3/interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) expression in CD4+ and CD3+ T cells from SLE mice and SLE patients, respectively We investigated fluctuations in gene expression in CD4+ T cells isolated from spleens of SLE-prone mice and in CD3+ T cells from peripheral blood mononuclear cells (PBMCs) of SLE patients

Summary

Introduction

We previously reported that JAK–STAT-pathway mediated regulation of IFN-regulatory factor genes could play an important role in SLE pathogenesis. SLE is a chronic inflammatory disease that affects multiple organs and is a representative autoimmune disease in humans It is characterised by the activation of dendritic cells, macrophage and lymphocytes, which results in the production of several high-affinity autoantibodies and formation of immune complexes. Multiple cytokines, including type I IFN [4, 5], type II IFN-γ [6], IL-2, and IL-6, play key roles in SLE initiation, progression, and development Each of these cytokines transmits signals via receptors controlled by the Janus kinase–signal transducer and activator of transcription (JAK–STAT)-signalling pathway [7]. Our findings suggested that JAK–STAT-pathway mediated regulation of IFN-regulatory factor (IRF)-related genes might contribute to SLE pathogenesis and disease activity [8]. Based on our previous findings regarding the role of IFN in SLE via the JAK–STAT pathway and the fact that TOFA comprises a multitargeted therapeutic, we evaluated the efficacy of TOFA as a novel SLE-treatment option

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