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

BMC Immunol. 2017 Aug 22;18(1):41. doi: 10.1186/s12865-017-0225-9.

Abstract

Background: We 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.

Results: We 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.

Conclusion: Modulation 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.

Keywords: Cytokines; Interferon; JAK–STAT pathway; Systemic lupus erythematosus; T cells; Translational research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism
  • Dexamethasone / pharmacology
  • Dexamethasone / therapeutic use
  • Down-Regulation / drug effects*
  • Down-Regulation / immunology
  • Female
  • Furans / pharmacology*
  • Furans / therapeutic use*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Janus Kinase Inhibitors / pharmacology
  • Janus Kinase Inhibitors / therapeutic use
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology
  • Mice
  • Mice, Inbred MRL lpr
  • Mice, Inbred NZB
  • Middle Aged
  • Proteins / genetics
  • Proteins / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • Young Adult

Substances

  • Anti-Inflammatory Agents
  • Cytokines
  • Furans
  • IFIT3 protein, human
  • Ifit3 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Janus Kinase Inhibitors
  • Proteins
  • 5-(tetradecyloxy)-2-furancarboxylic acid
  • Dexamethasone