Sis-25, a meroditerpenoid derivative with a cyclobutane scaffold, inhibits activated T cell proliferation by targeting GSK3β in vitro and in vivo

A series of novel scopariusicide derivatives were designed and synthesized starting from the main diterpenoid from the aerial parts of Isodon scoparius. Sis-25 was the most effective compound among them. The potential mechanism(s) of its immunosuppressive activity in vitro, as well as its effects on delayed type hypersensitivity (DTH) reaction and imiquimod-induced dermatitis in vivo were investigated in this study. Sis-25 inhibited anti-CD3/anti-CD28 mAbs, PHA or alloantigen-induced T cell proliferation without obvious cytotoxicity. Sis-25 was a highly selective inhibitor of GSK3-beta and inhibited the mTOR/p70S6K pathway but not the PI3K/Akt, p38 MAPK/ ERK 1/2 and JAK3/STAT5 pathways. Furthermore, Sis-25 significantly inhibited IFN-gamma, IL-6 and IL-17 expression but not IL-10 expression in activated T cells. Finally, Sis-25 treatment mitigated the DNFB-induced DTH reaction and ameliorated imiquimod-induced dermatitis. In summary, Sis-25 exerted significant immunosuppressive activity by targeting GSK3 beta in vitro and in vivo. Sis-25 may guide the design of new drugs for more effective and safer treatments of autoimmune diseases and provide new insight into developing utilizations of Isodon scoparius.

Automated summary

The study found that Sis-25 exhibited significant immunosuppressive activity by targeting GSK3 beta both in vitro and in vivo, inhibiting multiple signaling pathways and cytokine expression, effectively suppressing immune responses and dermatitis.