Therapeutic Effects of Tofacitinib on Pristane-Induced Murine Lupus

Overview

Journal Arch Rheumatol

Specialty Rheumatology

Date 2022 Aug 26

PMID 36017210

Authors

Jiayi Lin

Yaqin Zhang

Meihua Wang

Yang Zhang

Pin Li

Yingping Cao

Xuwei Yang

Affiliations

Soon will be listed here.

Abstract

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 22 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 12 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.

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References

Talaat R, Mohamed S, Bassyouni I, Raouf A . Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine. 2015; 72(2):146-53. DOI: 10.1016/j.cyto.2014.12.027. View

Litvak V, Ratushny A, Lampano A, Schmitz F, Huang A, Raman A . A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses. Nature. 2012; 490(7420):421-5. PMC: 3556990. DOI: 10.1038/nature11428. View

Deenick E, Avery D, Chan A, Berglund L, Ives M, Moens L . Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. J Exp Med. 2013; 210(12):2739-53. PMC: 3832925. DOI: 10.1084/jem.20130323. View

Wallace D, Furie R, Tanaka Y, Kalunian K, Mosca M, Petri M . Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2018; 392(10143):222-231. DOI: 10.1016/S0140-6736(18)31363-1. View

Sekigawa I, Naito T, Hira K, Mitsuishi K, Ogasawara H, Hashimoto H . Possible mechanisms of gender bias in SLE: a new hypothesis involving a comparison of SLE with atopy. Lupus. 2004; 13(4):217-22. DOI: 10.1191/0961203304lu1012ed. View

Taguchi N, Hashimoto Y, Naiki M, Farr A, Boyd R, Ansari A . Abnormal thymic expression of epithelial cell adhesion molecule (EP-CAM) in New Zealand Black (NZB) mice. J Autoimmun. 1999; 13(4):393-404. DOI: 10.1006/jaut.1999.0332. View

Harada T, Kyttaris V, Li Y, Juang Y, Wang Y, Tsokos G . Increased expression of STAT3 in SLE T cells contributes to enhanced chemokine-mediated cell migration. Autoimmunity. 2007; 40(1):1-8. DOI: 10.1080/08916930601095148. View

Yoshimura A, Ito M, Chikuma S, Akanuma T, Nakatsukasa H . Negative Regulation of Cytokine Signaling in Immunity. Cold Spring Harb Perspect Biol. 2017; 10(7). PMC: 6028070. DOI: 10.1101/cshperspect.a028571. View

Babon J, Kershaw N, Murphy J, Varghese L, Laktyushin A, Young S . Suppression of cytokine signaling by SOCS3: characterization of the mode of inhibition and the basis of its specificity. Immunity. 2012; 36(2):239-50. PMC: 3299805. DOI: 10.1016/j.immuni.2011.12.015. View

10.

Zecevic L, Karamehic J, Coric J, Stubljar D, Avdagic N, Selmanovic K . Potential Immune Biomarkers in Diagnosis and Clinical Management for Systemic Lupus Erythematosus. J Med Biochem. 2018; 37(2):163-171. PMC: 6294097. DOI: 10.1515/jomb-2017-0048. View

11.

Yu X, Cai B, Wang M, Tan P, Ding X, Wu J . Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality. Immunity. 2016; 45(5):1093-1107. PMC: 7128466. DOI: 10.1016/j.immuni.2016.10.001. View

12.

Ramirez-Velez G, Medina F, Ramirez-Montano L, Zarazua-Lozada A, Hernandez R, Llorente L . Constitutive phosphorylation of interferon receptor A-associated signaling proteins in systemic lupus erythematosus. PLoS One. 2012; 7(7):e41414. PMC: 3408474. DOI: 10.1371/journal.pone.0041414. View

13.

Coit P, Jeffries M, Altorok N, Dozmorov M, Koelsch K, Wren J . Genome-wide DNA methylation study suggests epigenetic accessibility and transcriptional poising of interferon-regulated genes in naïve CD4+ T cells from lupus patients. J Autoimmun. 2013; 43:78-84. PMC: 3790645. DOI: 10.1016/j.jaut.2013.04.003. View

14.

OShea J, Holland S, Staudt L . JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med. 2013; 368(2):161-70. PMC: 7604876. DOI: 10.1056/NEJMra1202117. View

15.

Kershaw N, Murphy J, Liau N, Varghese L, Laktyushin A, Whitlock E . SOCS3 binds specific receptor-JAK complexes to control cytokine signaling by direct kinase inhibition. Nat Struct Mol Biol. 2013; 20(4):469-76. PMC: 3618588. DOI: 10.1038/nsmb.2519. View

16.

Munroe M, Vista E, Guthridge J, Thompson L, Merrill J, James J . Proinflammatory adaptive cytokine and shed tumor necrosis factor receptor levels are elevated preceding systemic lupus erythematosus disease flare. Arthritis Rheumatol. 2014; 66(7):1888-99. PMC: 4128244. DOI: 10.1002/art.38573. View

17.

Goropevsek A, Gorenjak M, Gradisnik S, Dai K, Holc I, Hojs R . STAT5 phosphorylation in CD4 T cells from patients with SLE is related to changes in their subsets and follow-up disease severity. J Leukoc Biol. 2017; 101(6):1405-1418. DOI: 10.1189/jlb.5A0416-194R. View

18.

Satoh M, Kumar A, Kanwar Y, Reeves W . Anti-nuclear antibody production and immune-complex glomerulonephritis in BALB/c mice treated with pristane. Proc Natl Acad Sci U S A. 1995; 92(24):10934-8. PMC: 40545. DOI: 10.1073/pnas.92.24.10934. View

19.

Rizzi M, Lorenzetti R, Fischer K, Staniek J, Janowska I, Troilo A . Impact of tofacitinib treatment on human B-cells in vitro and in vivo. J Autoimmun. 2016; 77:55-66. DOI: 10.1016/j.jaut.2016.10.005. View

20.

Baker K, Isaacs J . Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis?. Ann Rheum Dis. 2017; 77(2):175-187. DOI: 10.1136/annrheumdis-2017-211555. View