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

• Published in: BMC immunology Vol. 18; no. 1; p. 41
• Main Authors: Ikeda, Keigo, Hayakawa, Kunihiro, Fujishiro, Maki, Kawasaki, Mikiko, Hirai, Takuya, Tsushima, Hiroshi, Miyashita, Tomoko, Suzuki, Satoshi, Morimoto, Shinji, Tamura, Naoto, Takamori, Kenji, Ogawa, Hideoki, Sekigawa, Iwao
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 22.08.2017; BioMed Central
• Subjects: Adult; Aged; Animals; Anti-DNA antibodies; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Antibodies; Arthritis; CD3 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; Cellular signal transduction; Comparative analysis; Cytokines; Cytokines - genetics; Cytokines - metabolism; Development and progression; Dexamethasone; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; DNA methylation; DNA microarrays; Down-Regulation - drug effects; Down-Regulation - immunology; Dual energy X-ray absorptiometry; Effector cells; Female; Furans - pharmacology; Furans - therapeutic use; Gene expression; Gene regulation; Genes; Genetic aspects; Health aspects; Humans; Immunological memory; Interferon; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Janus Kinase Inhibitors - pharmacology; Janus Kinase Inhibitors - therapeutic use; Kidneys; Kinases; Lupus; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lymphocytes; Lymphocytes T; Memory cells; Mice; Mice, Inbred MRL lpr; Mice, Inbred NZB; Middle Aged; Nephritis; Pathogenesis; Patients; Physiological aspects; Proteins - genetics; Proteins - metabolism; Proteinuria; Rodents; Signal transduction; Signal Transduction - drug effects; Spleen; Systemic lupus erythematosus; T-Lymphocyte Subsets - drug effects; T-Lymphocyte Subsets - immunology; Young Adult; Japan; Translational research; Interferon; Systemic lupus erythematosus; Cytokines; T cells; JAK–STAT pathway
• DOI: 10.1186/s12865-017-0225-9
• ISSN: 1471-2172

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. 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. 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.