Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses.

Abstract

OBJECTIVE:

SM934, an artemisinin derivative, possesses potent antiproliferative and antiinflammatory properties. The aim of this study was to examine the effects and explore the mechanisms of SM934 to treat autoimmune disease in lupus-prone female MRL/lpr mice.

METHODS:

In vitro, the effects of SM934 on the activation of polyclonal CD4+ T cells and the differentiation of naive CD4+ T cells were examined. In vivo, the preventative or therapeutic effects of SM934 in MRL/lpr mice were investigated. Ex vivo, the mechanisms of treatment were explored according to the immunologic correlates of disease.

RESULTS:

In vitro, SM934 inhibited interferon-γ (IFNγ) and interleukin-17 (IL-17) production from polyclonal CD4+ T cells activated by T cell receptor engagement and the differentiation of naive CD4+ T cells into Th1 and Th17 cells, but not Treg cells. In vivo, 12-week-old MRL/lpr mice treated with SM934 for 4 weeks showed significantly ameliorated proteinuria and renal lesion severity; decreased levels of blood urea nitrogen, serum IFNγ, and serum anti-double-stranded DNA antibodies; decreased spleen size; and a lower percentage of CD3+B220+CD4-CD8- T cells; 16-week-old MRL/lpr mice treated with SM934 for 8 weeks avoided severe proteinuria and survived longer. Ex vivo, SM934 treatment elevated the percentage of Treg cells, inhibited the development of Th1 and Th17 cells, and impeded the comprehensive activation of STAT-1, STAT-3, and STAT-5 proteins in splenocytes.

CONCLUSION:

Taken together, the results of this study demonstrated that the artemisinin analog SM934 had therapeutic effects in lupus-prone female MRL/lpr mice by inhibiting both Th1 cell and Th17 cell responses. Moreover, this study indicated that both IFNγ and IL-17 are required for the elicitation and development of murine lupus.

• Authors: Li-Fei Hou, Shi-Jun He, Xin Li, Yang Yang, Pei-Lan He, Yu Zhou, Feng-Hua Zhu, Yi-Fu Yang, Ying Li, Wei Tang, Jian-Ping Zuo
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 63 Issue 8 Pg. 2445-55 (Aug 2011) ISSN: 1529-0131 [Electronic] United States
• PMID: 21484768 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 by the American College of Rheumatology.

Chemical References

• Artemisinins
• beta-aminoarteether maleate
• Interferon-gamma

Topics

• Animals
• Artemisinins (pharmacology, therapeutic use)
• Disease Models, Animal
• Female
• Interferon-gamma (immunology)
• Lupus Erythematosus, Systemic (drug therapy, immunology)
• Mice
• Th1 Cells (drug effects, immunology)
• Th17 Cells (drug effects, immunology)
• Treatment Outcome