SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China.
International immunopharmacology (Impact Factor: 2.47). 09/2009; 9(13-14):1509-17. DOI: 10.1016/j.intimp.2009.09.003
Source: PubMed


In the present study, we investigated the immunosuppressive effects and underlying mechanisms of beta-aminoarteether maleate (SM934), a derivative of artemisinin, against T cell activation in vitro and in vivo. In vitro, SM934 significantly inhibited the proliferation of splenocytes induced by concanavalin A (Con A), lipopolysaccharide (LPS), mixed lymphocyte reaction (MLR), and anti-CD3 plus anti-CD28 (anti-CD3/28). SM934 significantly inhibited interferon (IFN)-gamma production and CD4(+) T cell division stimulated by anti-CD3/28. SM934 also promoted apoptosis of CD69(+) population in CD4(+) T cells stimulated by anti-CD3/28. Furthermore, SM934 inhibited interleukin (IL)-2 mediated proliferation and survival through blocking Akt phosphorylation in activated T cells. In ovalbumin (OVA)-immunized mice, oral administration of SM934 suppressed OVA-specific T cell proliferation and IFN-gamma production. SM934 treatment also significantly inhibited the sheep red blood cell (SRBC)-induced delayed type hypersensitivity (DTH) reactions in mice. Taken together, SM934 showed potent immunosuppressive activities in vitro and in vivo. Our results demonstrated that SM934 might be a potential therapeutic agent for immune-related diseases.

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    • "Similar to SM735, the studies in Zuo group in SIMM found SM905 possessed potent immunoregulatory properties [5] [6] [7]. However, SM934 is quite distinct [11]. Similar to SM905 and artemether, in vitro, SM934 significantly inhibited the proliferation and IFN-í µí»¾ production of splenocytes or purified CD4+ T cells induced by mixed lymphocyte reaction (MLR) or TCR cross-linking. "
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    • "Besides having antimalarial activity, artemisinin and its derivatives also exhibit potent immunosuppressive activity in several autoimmune disease models, including systemic lupus erythematosus [5]–[7], rheumatoid arthritis [8]–[11], and experimental autoimmune encephalomyelitis [12], [13]. Although the underlying mechanisms are not well-understood, artemisnin can inhibit the proliferation and differentiation of T cells [5], [14], [15]. Artemisinin analogs have been shown to suppress the differentiation of both Th1 and Th17 cells and induce the development of Treg cells in vitro and in vivo [6], [10], [13], [16]. "
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    • "SM934 treatment could significantly increase Treg percentage and suppress the Th1 and Th17 responses in NZB/W F1 mice. Although our previous report suggested that SM934 could induce activated CD4+ T cells into apoptosis in vitro [34], it's hardly to present such effects of SM934 in vivo, for that, usually apoptotic cells will be phagocytized and cleared quickly. Herein, through flow cytometric staining surface B220 and western blot analysis of Bcl-2 protein expression in the CD4+ T cells, we firstly demonstrated that SM934 treatment could prompt the apoptosis of activated CD4+ T cells in vivo. "
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    ABSTRACT: Artemisinin 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 F(1) mice. NZB/W F(1) 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 F(1) 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 F(1) mice. In addition, SM934 treatment promoted the IL-10 production of macrophages from NZB/W F(1) 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. The results of this study demonstrated that artemisinin analogue SM934 had therapeutic effects on lupus-prone female NZB/W F(1) mice by inhibiting the pathogenic helper T cell development and enhancing anti-inflammatory cytokine IL-10 production.
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