Hou Li-Fei, He Shi-Jun, Li Xin, Yang Yang, He Pei-Lan, Zhou Yu, Zhu Feng-Hua, Yang Yi-Fu, Li Ying, Tang Wei, Zuo Jian-Ping
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Arthritis Rheum. 2011 Aug;63(8):2445-55. doi: 10.1002/art.30392.
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.
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.
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.
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.
青蒿素衍生物SM934具有强大的抗增殖和抗炎特性。本研究旨在探讨SM934治疗狼疮易感雌性MRL/lpr小鼠自身免疫性疾病的效果并探索其机制。
在体外,检测SM934对多克隆CD4+ T细胞活化及初始CD4+ T细胞分化的影响。在体内,研究SM934对MRL/lpr小鼠的预防或治疗作用。离体实验中,根据疾病的免疫相关性探索治疗机制。
在体外,SM934抑制T细胞受体激活的多克隆CD4+ T细胞产生干扰素-γ(IFNγ)和白细胞介素-17(IL-17)以及初始CD4+ T细胞向Th1和Th17细胞的分化,但不影响调节性T细胞(Treg细胞)。在体内,12周龄的MRL/lpr小鼠用SM934治疗4周后,蛋白尿和肾损伤严重程度显著改善;血尿素氮、血清IFNγ和血清抗双链DNA抗体水平降低;脾脏大小减小;CD3+B220+CD4-CD8- T细胞百分比降低;16周龄的MRL/lpr小鼠用SM934治疗8周后避免了严重蛋白尿并存活更长时间。离体实验中,SM934治疗提高了Treg细胞百分比,抑制了Th1和Th17细胞的发育,并阻碍了脾细胞中STAT-1、STAT-3和STAT-5蛋白的全面激活。
综上所述,本研究结果表明青蒿素类似物SM934通过抑制Th1细胞和Th17细胞反应,对狼疮易感雌性MRL/lpr小鼠具有治疗作用。此外,本研究表明IFNγ和IL-17都是小鼠狼疮诱发和发展所必需的。