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Therapeutic Effects of Tofacitinib on Pristane-Induced Murine Lupus
Jiayi Lin1, Yaqin Zhang1, Meihua Wang1
1Department of Laboratory Medicine, Fujian Medical University Union Hospital, Fuzhou, China.
Objectives:
This study aims to investigate the effectiveness of tofacitinib, a Janus kinase (JAK) 1/JAK3 inhibitor, in treating murine lupus, and also explore 12 related genes downstream of JAK-signal transducer and activator of transcription (STAT) signaling pathways to find the underlying mechanism.
Materials And Methods:
This study was conducted between July 2017 and January 2020. Fifty-seven female BALB/c mice (aging 8 to 10 weeks old; weighing 18 to 20 g) were assigned to a saline control (SC) group and a pristane-induced lupus group. The latter included four groups, namely, pristane control (PC), tofacitinib (T), methylprednisolone (MP), and tofacitinib plus methylprednisolone (T+MP). Animal models of lupus were induced with pristane, whereas SC mice were treated with normal saline. From the 22nd week after induction, each group was given the aforementioned corresponding intervention for 11 weeks. The following variables were tested: serum concentrations of anti-double-stranded deoxyribonucleic acid (anti-dsDNA), interleukin 6 (IL-6), and interferon gamma (IFN-γ); number of regulatory T (Treg) cells; messenger ribonucleic acid levels of forkhead box P3 and 12 related genes downstream of JAK-STAT pathway; and renal impairment.
Results:
Red swollen joints and proteinuria were first observed in PC after the 12th week. After treatment, T, MP, and T+MP showed relieved red swollen joints and splenomegaly, as well as decreased urine protein, anti-dsDNA, IL-6, IFN-γ, Treg cells, pathological scores, and hyperplasia of mesangial matrix in glomeruli compared with PC. The IFN regulatory factor 7 level was higher in T+MP (p0.05) and MP (p>0.05) than in PC after treatment. The expression of suppressor of cytokine signaling (SOCS) 1 was lower in T (p>0.05), T+MP (p0.05) than in PC. The SOCS3 level was higher in T (p>0.05) and T+MP (p0.05) than in PC.
Conclusion:
Tofacitinib can ameliorate glomerulonephritis and arthritis in a pristane-induced murine model of lupus. SOCS3 gene may be involved in the therapeutic mechanism of tofacitinib.
Insights
Tofacitinib effectively treats lupus in mice by reducing joint swelling and kidney damage. The study suggests the SOCS3 gene plays a role in tofacitinib's therapeutic effects, offering insights into lupus treatment.
Area of Science:
- Immunology
- Pharmacology
- Genetics
Background:
- Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by inflammation and damage to various organs.
- Murine models are crucial for understanding SLE pathogenesis and evaluating potential therapeutic agents.
- Janus kinase (JAK) inhibitors, like tofacitinib, modulate immune responses by targeting intracellular signaling pathways.
Purpose of the Study:
- To evaluate the efficacy of tofacitinib in a pristane-induced murine model of lupus.
- To investigate the underlying molecular mechanisms of tofacitinib's action by examining JAK-STAT pathway-related genes.
- To compare the effects of tofacitinib with methylprednisolone and their combination.
Main Methods:
- Fifty-seven female BALB/c mice were induced with pristane to model lupus.
- Treatment groups included saline control, pristane control, tofacitinib, methylprednisolone, and a combination therapy.
- Key parameters assessed included autoantibodies (anti-dsDNA), cytokines (IL-6, IFN-γ), regulatory T cells, JAK-STAT pathway gene expression, and renal pathology.
Main Results:
- Tofacitinib, methylprednisolone, and combination therapy significantly reduced lupus symptoms such as joint swelling, proteinuria, and splenomegaly compared to controls.
- These treatments decreased levels of anti-dsDNA, IL-6, IFN-γ, and regulatory T cells.
- Gene expression analysis indicated altered levels of IFN regulatory factor 7, SOCS1, and SOCS3, with SOCS3 potentially mediating tofacitinib's effects.
Conclusions:
- Tofacitinib demonstrates significant therapeutic benefits in a murine lupus model, ameliorating arthritis and glomerulonephritis.
- The study highlights the involvement of the SOCS3 gene in the mechanism of action for tofacitinib in lupus treatment.
- These findings support further investigation of JAK inhibitors for SLE management.
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