Withasteroid B from D. metel L. regulates immune responses by modulating the JAK/STAT pathway and the IL-17+ RORγt+ /IL-10+ FoxP3+ ratio

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Abstract

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 (T reg) 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.

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Kevin S. Carbajal, John DiGiovanni, Paul K S Chan … (2004)

Here we report that epidermal keratinocytes in psoriatic lesions are characterized by activated Stat3. Transgenic mice with keratinocytes expressing a constitutively active Stat3 (K5.Stat3C mice) develop a skin phenotype either spontaneously, or in response to wounding, that closely resembles psoriasis. Keratinocytes from K5.Stat3C mice show upregulation of several molecules linked to the pathogenesis of psoriasis. In addition, the development of psoriatic lesions in K5.Stat3C mice requires cooperation between Stat3 activation in keratinocytes and activated T cells. Finally, abrogation of Stat3 function by a decoy oligonucleotide inhibits the onset and reverses established psoriatic lesions in K5.Stat3C mice. Thus, targeting Stat3 may be potentially therapeutic in the treatment of psoriasis.