ABSTRACT
Cimicifuga simplex is a medicinal herb which has a wide range of biological activities. We isolated seven 9,19-cycloartenol glycosides from the roots of C. simplex, and among the glycosides, G3 exhibited the strongest inhibitory effect on immune responses, including suppressing the differentiation of CD4+ T cells and directly suppressing the cytokine-induced JAK/STAT signaling pathways. In the IL-23-induced mouse ear model of skin disease, G3 repressed disease development by inhibiting the expression of pro-inflammatory mediators in murine ear skin. Moreover, G3 affected the maturation of DCs in vitro, thereby inducing T cell differentiation, resulting in an increased Treg phenotype and decreased Th17 phenotype. This study provides new evidence that G3 might ameliorate chronic inflammatory skin diseases by suppressing pathogenic CD4+ T cell differentiation and the IL-17+RORγt+/IL-10+FoxP3+ ratio. These findings suggest that G3 might mediate the therapeutic effects observed in psoriasis patients following treatment with C. simplex.
Subject(s)
Cimicifuga/chemistry , Glycosides/chemistry , Glycosides/pharmacology , T-Lymphocytes, Regulatory/cytology , Th17 Cells/cytology , Animals , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Cimicifuga/metabolism , Cytokines/pharmacology , Disease Models, Animal , Female , Forkhead Transcription Factors/metabolism , Glycosides/therapeutic use , Interleukin-17/metabolism , Mice , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Plant Roots/chemistry , Plant Roots/metabolism , Signal Transduction/drug effects , Skin Diseases/drug therapy , Skin Diseases/pathology , Spleen/cytology , Spleen/drug effects , Spleen/metabolism , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/drug effects , Th17 Cells/metabolismABSTRACT
Datura metel L. is a medicinal herb that contains withasteroids and has a wide range of biological activities. We isolated seven withasteroids from the flowers of D. metel L and examined their ability to inhibit immune responses in vitro and in vivo. Among the withasteroids, withasteroid B2 exhibited the strongest inhibitory effect on immune responses comparing B2 with other isolated compounds from D. metel L., including suppressing the differentiation of CD4+ T cells by inhibiting the expression and production of T cell lineage-specific master regulators and cytokines and directly suppressing the cytokine-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathways. In the interleukin (IL)-23-induced mouse ear model of skin disease, B2 repressed disease development by inhibiting the expression of proinflammatory mediators in murine ear skin. Moreover, B2 affected the maturation of dendritic cells (DCs) in vitro which, in turn, induced T cell differentiation with an increased regulatory T cell (Treg ) phenotype and decreased T helper type 17 (Th17) phenotype. This study provides new evidence that B2 might ameliorate chronic inflammatory skin diseases by suppressing pathogenic CD4+ T cell differentiation and the IL-17+ retinoic-acid-receptor-related orphan receptor gamma t (RORγt)+ /IL-10+ forkhead box protein 3 (FoxP3)+ ratio. These findings suggest that B2 might mediate the therapeutic effects observed in psoriasis patients following treatment with D. metel L.