SM934 Treated Lupus-Prone NZB×NZW F1 Mice by Enhancing Macrophage Interleukin-10 Production and Suppressing Pathogenic T Cell Development

Li-Fei Hou,Xiao-Hui Zhang,Ying Li,Chun-Ping Wan,Pei-Lan He,Yang Yang,Xin Li,Yu Zhou,Yi-Fu Yang,Feng-Hua Zhu,Jian-Ping Zuo,Wei Tang,Shi-Jun He,Amr H Sawalha

doi:10.1371/journal.pone.0032424

Abstract

BackgroundArtemisinin and its derivatives were reported to possess strong regulatory effects on inflammation and autoimmune diseases. This study was designed to examine the therapeutic effects and underlying mechanisms of SM934, a water-soluble artemisinin analogue, on lupus-prone female NZB×NZW F1 mice.Methodology/Principal FindingsNZB/W F1 mice were treated orally with SM934 for 3 or 6 months respectively to investigate the effect on clinical manifestations and immunological correlates. To further explore the mechanisms of SM934, ovalbumin (OVA)-immunized or interferon (IFN)-γ-elicited C57BL/6 mice were used. In vivo, treatment with SM934 for 3 or 6 months significantly delayed the progression of glomerulonephritis and increased the survival rate of NZB/W F1 mice. Clinical improvement was accompanied with decreased Th1-related anti-double-strand DNA (dsDNA) IgG2a and IgG3 Abs, serum interleukin (IL)-17, and increased Th2-related anti-dsDNA IgG1 Ab, serum IL-10 and IL-4. SM934 treatment also suppressed the accumulation of effector/memory T cells, induced the apoptosis of CD4+ T cells, while enhancing the development of regulatory T cells in NZB/W F1 mice. In addition, SM934 treatment promoted the IL-10 production of macrophages from NZB/W F1 mice, OVA-immunized C57BL/6 mice and IFN-γ-elicited C57BL/6 mice. In vitro, SM934 enhanced IL-10 production from primary macrophages stimulated with IFN-γ.Conclusions/SignificanceThe results of this study demonstrated that artemisinin analogue SM934 had therapeutic effects on lupus-prone female NZB/W F1 mice by inhibiting the pathogenic helper T cell development and enhancing anti-inflammatory cytokine IL-10 production.

Highlights

Conclusions/Significance: The results of this study demonstrated that artemisinin analogue SM934 had therapeutic effects on lupus-prone female NZB/W F1 mice by inhibiting the pathogenic helper T cell development and enhancing antiinflammatory cytokine IL-10 production
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal accumulation of autoreactive T lymphocytes and production of autoantibody against self-antigen, which result in the development of immune complex-mediated glomerulonephritis and renal failure [1,2]
We explored the therapeutic effects and mechanisms of SM934 on autoimmune syndrome in lupus-prone female NZB/W F1 mice

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by abnormal accumulation of autoreactive T lymphocytes and production of autoantibody against self-antigen, which result in the development of immune complex-mediated glomerulonephritis and renal failure [1,2]. Female NZB/W F1 mice resemble human lupus closely. This strain of mice spontaneously develops severe autoimmune disease, especially the fatal immune complex-mediated glomerulonephritis, around 5 to 7 months of age, and approximately 50% die by 8 months and 90% die by 12 months of age [3,4]. It’s well documented that activated/memory helper T cells (CD4+CD44+CD62L2 effector T cells, Teff), especially IFN-c-producing Th1 subset, are responsible for inciting human and murine lupus, in part through increased production of highly nephritogenic Th1-related Ig2a and IgG3 autoantibodies [5,6,7,8]. This study was designed to examine the therapeutic effects and underlying mechanisms of SM934, a water-soluble artemisinin analogue, on lupus-prone female NZB6NZW F1 mice

Methods

Results

Conclusion