Investigation of the immunosuppressive activity of artemether on T‐cell activation and proliferation

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Abstract
Background and purpose: Artemisinin and its derivatives exhibit potent immunosuppressive activity. The purpose of the current study was to examine the immunosuppressive activity of artemether directly on T lymphocytes and to explore its potential mode of action. Experimental approach: In vitro, T‐cell proliferation was measured using [3H]‐thymidine incorporation assay in cells stimulated with ConA, alloantigen and anti‐CD3 antibody. CFSE‐labeled cell division and cell cycle distribution were monitored by flow cytometry. In vivo, the effects of artemether were evaluated in delayed‐type hypersensitivity (DTH) and purified T‐cell responses to ovalbumin in ovalbumin‐immunized mice. The activation of extracellular signal‐regulated kinase1/2 (ERK1/2) and Raf1 were assessed by Western blot analysis and the activation of Ras was tested in pull‐down assays. Key results: We show that, in vitro, artemether suppressed ConA‐ or alloantigen‐induced splenocyte proliferation, influenced production of the cytokines IL‐2 and IFN‐γ and inhibited cell cycle progression through the G0/G1 transition. In vivo, administration of artemether attenuated CD4 T‐cell‐mediated DTH reaction, and suppressed antigen‐specific T‐cell response in immunized mice. Further experiments showed that, treatment with artemether impaired both antigen‐ and anti‐CD3‐induced phosphorylation of ERK. In primary T cells, artemether profoundly inhibited anti‐CD3‐induced phosphorylation of Raf1 and activation of Ras. Conclusions and implications: This study provided experimental evidence of the immunosuppressive effects of artemether directly on T cells both in vitro and in vivo. Its immunosuppressive mechanism involved inhibition of the activation of the Ras‐Raf1‐ERK1/2 protein kinase cascade in T cells. British Journal of Pharmacology (2007) 150, 652–661. doi:10.1038/sj.bjp.0707137