1. Sis-25, a meroditerpenoid derivative with a cyclobutane scaffold, inhibits activated T cell proliferation by targeting GSK3β in vitro and in vivo.
- Author
-
Liu, Yang, Li, Xingren, Wu, Xiuyin, Luo, Xingyan, Yan, Bingchao, Mo, Chunfen, Guo, Huijie, Yang, Shuxia, Wang, Yantang, Lai, Yi, Puno, Pematenzin, and Li, Limei
- Subjects
- *
T cells , *CYCLOBUTANE derivatives , *CELL proliferation , *INHIBITION of cellular proliferation , *DELAYED hypersensitivity , *CYCLOBUTANE , *BONE regeneration - Abstract
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-β 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-γ, 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 GSK3β 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. [Display omitted] • Sis-25 inhibits T cell proliferation without obvious cytotoxicity. • Sis-25 is identified as a highly selective inhibitor of GSK3-β. • Inhibition of GSK3-β by its inhibitor LiCl or SB415286 promotes T cell activation, but inhibits T cell proliferation. • Sis-25 treatment mitigates DNFB-induced DTH reaction and ameliorates imiquimod-induced dermatitis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF