A novel Pseudolaric acid B derivative, Hexahydropseudolaric acid B, exterts an immunomodulatory effect in vitro/in vivo evaluation.

Abstract Identification of immunosuppressants from natural sources has a proven track record in immune mediated disorders. Pseudolaric acid B is a diterpenoid isolated from the roots of Pseudolarix amabilis , possessing potent immunomodulatory effect. However, the cytotoxicity limits its future clinical application. The purpose of this study was to investigate the immunosuppressive activity of Hexahydropseudolaric acid B, a Pseudolaric acid B derivative, on T cell-mediated immune response both in vitro and in vivo , and investigated its immunomodulatory effect to develop a more ascendant immunosuppressive agent. The results showed that Hexahydropseudolaric acid B could exert more preferable immunosuppressive activity and lower cytotoxicity than Pseudolaric acid B. Hexahydropseudolaric acid B significantly inhibited T cell proliferation activated by mitogen and alloantigen without obvious cytotoxicity in vitro . Furthermore, Hexahydropseudolaric acid B could ameliorate ear swelling in a mouse model of 2,4-dinitrofluorobenzene-induced delayed-type hypersensitivity in vivo . Mechanistic study revealed that Hexahydropseudolaric acid B could enhance regulatory T cells via promoting Foxp3 expression and TGF-β level, accompanied by attenuating Akt activation, blocking p38MAPK/MK2-HSP27 signal cascades, and up-regulating PPAR-γ expression. Taken together, these results suggest that Hexahydropseudolaric acid B exerts more preferable immunosuppressive activity than its precursor Pseudolaric acid B by affecting multiple targets, which support the need for continued efforts to characterize the efficacy of HPAB as a promising and safe candidate to treat immune-related diseases.