Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Abstract Background: Systemic lupus erythematosus (SLE), a devastating autoimmune disorder, results from the aberrant T cell and B cell activation. Norcantharin(NCTD), a derivative of Cantharidin, is an efficacious anti-cancer drug, whereas the role of NCTD in SLE remains unknown. As a result, we aimed to investigate the therapeutic effect of NCTD on the development of murine lupus.Methods: MRL/MpJ and MRL/ lpr female mice were randomly divided into three groups and administered with vehicle control or NCTD at 1 mg/kg or 2 mg/kg. The mortality rate, auto-antibodies, kidney damage, immune complex deposition and lupus-related inflammation level were tested. Furthermore, the proportion of T/B cells or T cell subsets in splenocytes from each group was monitored using flow cytometry. Finally, double-negative (CD3+CD4-CD8-, DN) T cell proliferation and T helper 17 (Th17) cell differentiation in vitro as well as regulatory pathways were analyzed for NCTD treatment.Results: NCTD decreased mortality, the accumulation of anti-dsDNA, splenomegaly and inflammation level of lupus mice. In addition, NCTD-treated MRL/ lpr mice showed notably ameliorated renal involvement. Moreover, we found that NCTD reduced DN T cell proliferation and Th17 differentiation via mediating the activation of signal transducer and activator of transcription 3 (STAT3). Conclusions: NCTD effectively suppressed DN T cell proliferation and Th17 cell polarization, thus ultimately contributing to the attenuated the SLE development. Our results revealed that NCTD may be a promising therapeutic agent for SLE.