Dihydroartemisinin inhibits activation of the Toll-like receptor 4 signaling pathway and production of type i interferon in spleen cells from lupus-prone MRL/lpr mice

摘要

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by various immunological abnormalities. Dihydroartemisinin (DHA), a metabolite of artemisinin, has been recently reported to exhibit immunosuppressive properties. The present study aims to determine the effects of DHA on spleen cell activation triggered by lipopolysaccharide (LPS) and investigate the effects of DHA on LPS-induced activation of the Toll-like receptor 4 (TLR4)/interferon regulatory factor (IRF) signaling pathway. Spleen cells from lupus-prone MRL/lpr mice were isolated, prepared and cultured. Cells were treated with LPS alone or LPS with DHA, and spleen cell proliferation was analyzed using MTS assay. Protein expressions of TLR4, IRF3, and IRF7 were analyzed by Western blot. IRF3 phosphorylation was also determined. Gene expression levels of IFN-α and IFN-β were measured using real-time PCR, and protein levels in cells' supernatants were determined by ELISA. DHA was found to inhibit LPS-induced spleen cell proliferation, decrease LPS-induced protein expression of TLR4, and inhibit IRF3 phosphorylation. Furthermore, LPS significantly induced IRF3 expression and slightly increased IRF7 expression in the nucleus of spleen cells, which was accompanied by enhanced IFN-α and IFN-β production. DHA inhibited the effects of LPS in spleen cells of MRL/lpr mice. Taken together, the data obtained reveal that DHA inhibits LPS-induced cell activation possibly by suppressing the TLR4/IRF/IFN pathway in spleen cells of MRL/lpr mice. These data suggest that DHA has the potential therapeutic utility for the treatment of SLE.