Alantolactone Suppresses Proliferation and the Inflammatory Response in Human HaCaT Keratinocytes and Ameliorates Imiquimod-Induced Skin Lesions in a Psoriasis-Like Mouse Model.

Wen-Ho Chuo,Chi-Chien Lin,Chao-Liang Wu,Nicole R Bracci,Hung-Yi Huang,Yu-Kang Chang,Yu-Tang Tung

doi:10.3390/life11070616

Abstract

Psoriasis is an immune-mediated inflammatory disease that affects 2% to 3% of the world population. Alantolactone, a sesquiterpene lactone, was isolated from Inula helenium and Radix inulae and has several biological effects, including antifungal, anthelmintic, antimicrobial, anti-inflammatory, antitrypanosomal, and anticancer properties. This study aimed to evaluate the antipsoriatic potential of alantolactone in vitro and in vivo and to explore its underlying mechanisms. These results showed that alantolactone significantly attenuated IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α (M5) cytokine-induced hyperproliferation in HaCaT keratinocytes. Moreover, M5 cytokines significantly upregulated the mRNA levels of TNF-α, IL-6, IL-1β, and IL-8. However, alantolactone attenuated the upregulation of these inflammatory cytokines. In addition, alantolactone was found to inhibit STAT3 phosphorylation and NF-κB p65 nuclear translocation in HaCaT keratinocytes. Furthermore, alantolactone treatment in mice significantly alleviated the severity of skin lesions (erythema, scaling and epidermal thickness, and inflammatory cell infiltration) and decreased the mRNA expression of inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, IL-8, IL-17A, and IL-23) in an IMQ-induced-like mouse model. Therefore, our new findings revealed that alantolactone alleviates psoriatic skin lesions by inhibiting inflammation, making it an attractive candidate for future development as an antipsoriatic agent.

Highlights

Psoriasis is a common chronic inflammatory skin disease that affects 2% to 3% of the world population [1]
The results showed that M5 cytokines can induce HaCaT keratinocytes to generate some characteristics of psoriatic keratinocytes
The present study showed that alantolactone decreased the mRNA levels of TNF-α, IL-6, IL-1β, IL-8, IL-17A, and IL-23, thereby suppressing Th1- and Th17-mediated cytokines and improving IMQ-induced psoriasis-like skin lesions and inflammation status in mice

Summary

Introduction

Psoriasis is a common chronic inflammatory skin disease that affects 2% to 3% of the world population [1]. Psoriasis is characterized by the excessive proliferation and abnormal differentiation of keratinocytes and excessive immune-cell infiltration in the dermis and epidermis [2]. The exact pathogenesis of psoriasis remains unclear, but it is a common immune-mediated disease believed to result from abnormal crosstalk between keratinocytes and immune cells [3]. Various cytokines secreted by immune cells stimulate keratinocytes, which may lead to keratinocyte hyperproliferation. Hyperproliferative keratinocytes respond to these cytokines by producing massive amounts of proinflammatory cytokines, thereby sustaining or even amplifying the inflammatory response [4,5,6,7]. Reducing keratinocyte hyperproliferation and/or excessive inflammation is useful for the treatment of psoriasis

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