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Sis-25, a meroditerpenoid derivative with a cyclobutane scaffold, inhibits activated T cell proliferation by targeting GSK3β in vitro and in vivo.
- Source :
-
European Journal of Pharmacology . Aug2022, Vol. 929, pN.PAG-N.PAG. 1p. - Publication Year :
- 2022
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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]
Details
- Language :
- English
- ISSN :
- 00142999
- Volume :
- 929
- Database :
- Academic Search Index
- Journal :
- European Journal of Pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 158116890
- Full Text :
- https://doi.org/10.1016/j.ejphar.2022.175151