Dihydroartemisinin derivative DC32 attenuates collagen-induced arthritis in mice by restoring the Treg/Th17 balance and inhibiting synovitis through down-regulation of IL-6.

Imbalance of Treg/Th17 and chronic synovitis characterized by the recruitment and infiltration of inflammatory cells are the typical features of rheumatoid arthritis (RA). IL-6 promotes the differentiation and function of Th17 cells, which contributes to the imbalance of Treg/Th17 and aggravates lymphocytic infiltration in joints. DC32, a dihydroartemisinin derivative, was found to have anti-inflammatory and immunosuppressive activities in previous study. The aim of this study is to evaluate the effects and mechanisms of DC32 in immunodeficiency and inflammatory infiltration of RA. In vivo, the antirheumatic effect of DC32 was evaluated in a collagen-induced arthritis (CIA) mouse model in DBA/1 mice. The percentages of Treg and Th17 and transcription of IL-6 in the spleen were assayed. In vitro, a coculture system of ConA-activated lymphocytes and fibroblast-like synoviocytes (FLSs) from rat with adjuvant arthritis (AA) was established. The effects and mechanisms of DC32 on synovitis were investigated. It was shown that DC32 inhibited footpad swelling and lymphocytic infiltration in mice with CIA and significantly restored the Treg/Th17 balance by reducing the transcription of IL-6 in splenocytes. DC32 significantly inhibited the lymphocyte-induced invasion and migration of FLSs by decreasing the secretion of MMPs (MMP-2, MMP-3) in vitro. DC32 also reduced the transcription of chemokines (CXCL12, CX3CL1) and IL-6 in FLSs, as well as IL-6 levels in the supernatant. These results demonstrated that DC32 may attenuate RA by restoring Treg/Th17 balance and inhibiting lymphocytic infiltration through downregulation of the expression and transcription of IL-6. This study supports the potential of DC32 to down-regulate IL-6 for the treatment of RA and other related autoimmune diseases.