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Pseudolaric acid B attenuates atopic dermatitis-like skin lesions by inhibiting interleukin-17-induced inflammation.

ABSTRACT: Pseudolaric acid B (PB), isolated from the extract of the root bark of Pseudolarix kaempferi Gordon, has been used as a traditional remedy for the treatment of skin diseases. However, the information of PB on atopic dermatitis (AD) remains largely unknown. In the present study, oral administration with PB improved the severity scores of AD-like skin lesions dose-dependently in NC/Nga mice through reducing serum IgE, pro-inflammatory cytokines, and the infiltration of inflammatory cells. In addition, PB significantly attenuated the levels of IL-17 and IL-22, and the proportion of Th17 cells in NC/Nga mice, as well as decreased IL-17-induced inflammation in RAW264.7 cells. Moreover, PB inhibited the phosphorylation of IκBα and miR-155 expression both in NC/Nga mice and in IL-17-stimulated RAW264.7 cells, which could be reversed by GW9662, a specific antagonist for PPARγ. The incorporation of GW9662 reversed the inhibitory effect of PB on the RORγ-mediated activation of the Il17 promoter. Transfection with PPARγ luciferase reporter gene further demonstrated the enhancement of PB on PPARγ transactivation. These findings indicate that PB could ameliorate AD-like skin lesions by inhibiting IL-17-induced inflammation in a PPARγ-dependent manner, which would provide experimental evidence of PB for the therapeutic potential on AD and other inflammatory skin diseases.

SUBMITTER: Yang Z

PROVIDER: S-EPMC5554149 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Project description:Atopic dermatitis (AD), also known as atopic eczema, is one of the most common skin diseases and is characterized by allergic skin inflammation, redness, and itchiness and is associated with a hyperactivated type 2 immune response. The leading causes of AD include an imbalance in the immune system, genetic predisposition, or environmental factors, making the development of effective pharmacotherapies complex. Steroids are widely used to treat AD; however, they provide limited efficacy in the long term and can lead to adverse effects. Thus, novel treatments that offer durable efficacy and fewer side effects are urgently needed. Here, we investigated the therapeutic potential of Huangbai Liniment (HB), a traditional Chinese medicine, using an experimental AD mouse model, following our clinical observations of AD patients. In both AD patient and the mouse disease model, HB significantly improved the disease condition. Specifically, patients who received HB treatment on local skin lesions (3-4 times/day) showed improved resolution of inflammation. Using the 1-Chloro-2,4-dinitrobenzene (DNCB)-induced AD model in BALB/c mice, we observed that HB profoundly alleviated severe skin inflammation and relieved the itching. The dermatopathological results showed markedly reversed skin inflammation with decreased epidermal thickness and overall cellularity. Correspondingly, HB treatment largely decreased the mRNA expression of proinflammatory cytokines, including IL-1β, TNF-α, IL-17, IL-4, and IL-13, associated with declined gene expression of IL-33, ST2, and GATA3, which are connected to the type 2 immune response. In addition, HB restored immune tolerance by promoting regulatory T (TREG) cells and inhibiting the generation of TH1, TH2, and TH17 cells in vitro and in the DNCB-induced AD mouse model. For the first time, we demonstrate that HB markedly mitigates skin inflammation in AD patients and the DNCB-induced AD mouse model by reinvigorating the T cell immune balance, shedding light on the future development and application of novel HB-based therapeutics for AD.

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Pseudolaric acid B attenuates atopic dermatitis-like skin lesions by inhibiting interleukin-17-induced inflammation.

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