The new water‐soluble artemisinin derivative SM905 ameliorates collagen‐induced arthritis by suppression of inflammatory and Th17 responses

Abstract

Background and purpose: Our previous study showed that SM905, a novel artemisinin derivative, exhibited potent immunosuppressive activity. In this study, we evaluate preventive and therapeutic effect of SM905 on collagen-induced arthritis (CIA) in DBA/1 mice, and investigate its mechanisms both in inflammatory and autoimmune aspects of the disease. Experimental approach: CIA was induced by type II bovine collagen (CII) in DBA/1 mice. SM905 was given orally either before (continuously 1 day before booster immunization) or after disease onset (continuously 14 days after booster immunization). Disease incidence and severity were monitored, mRNA expression of proinflammatory mediators was determined by real-time PCR, purified T cell proliferation was assessed using [ 3 H]-thymidine incorporated assay, and T helper (Th) 17/Th1/Th2 type cytokine production was examined by ELISA. Key results: Oral treatment with SM905 delayed disease onset, reduced arthritis incidence and severity, and suppressed the enhanced expression of pro-inflammatory cytokines, chemokines and chemokine receptors in draining lymph nodes. The CII-induced T cell proliferation and production of interleukin (IL)-17A by T cells were strikingly inhibited. Correspondingly, the mRNA expression of IL-17A and RORgt (a specific transcription factor for Th17) was also reduced. This effect was coupled with a striking reduction of IL-6 production, which has a critical role in Th17 development. In established arthritis, SM905 profoundly inhibited disease progression, reduced IL-17A and RORgt mRNA expression, and suppressed pro-inflammatory mediator expression in arthritic joints. Conclusions and implications: SM905 had beneficial effects on CIA by suppressing inflammatory and pathogenic Th17 responses.

Recent advances in neutralizing the IL-6 pathway in arthritis

“…81 The results of this study supported the view that amelioration of CIA could be accomplished only by reducing the levels of both Th17 and IL-6.…”

Oral administration of artemisinin analog SM934 ameliorates lupus syndromes in MRL/lpr mice by inhibiting Th1 and Th17 cell responses

“…In contrast, in vivo SM934 could significantly suppress the Th1-mediated delayed-type hypersensitivity reaction even at a dosage of 1 mg/kg/day (27). Moreover, our previous studies demonstrated that artemisinin derivatives possessed therapeutic effects on collagen-induced arthritis by suppressing pathogenic Th17 cell responses (26).…”

“…However, most artemisinin derivatives possess poor water solubility or low bioavailability, which limits their further applications to treat autoimmune diseases. Several series of new artemisinin derivatives have been synthesized, and the water-soluble artemisinin derivative SM934 showed higher bioavailability, better bioactivity, and lower toxicity (25)(26)(27)(28). The acute toxicity of SM934 was tested in mice, and the median lethal dose was ϳ2 gm/kg.…”

Qinghaosu (artemisinin): Chemistry and pharmacology

“…At last, SM 735, SM 905, SM 933, and SM 934 ( Figure 2) were selected and tested in the animal models for 2,4-dinitrofluorobenzene (DNFB)-induced delayed-type hypersensitivity (DTH) reaction, sheep red blood cell (SRBC)-induced antibody production, and experimental autoimmune encephalomyelitis (EAE). Up to date, a number of papers related their immuno-suppressive activity and possible mechanisms have been published mainly from this Institute [55][56][57][58][59][60][61][62][63][64] . The preclinical research of SM 934 is in progress.…”