Acitretin inhibits IL-17A-induced IL-36 expression in keratinocytes by down-regulating IκBζ
Acitretin inhibits IL-17A-induced IL-36 expression in keratinocytes by down-regulating IκBζ
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阿维A通过下调 IγBγ 抑制角质形成细胞中 IL-17A 诱导的 IL-36 表达
DOI：
10.1016/j.intimp.2019.106045
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Yin, ZhiQiang
中科院分区：
文献类型：
--
作者：
Tu, Jie;Yin, Zhi;Yin, ZhiQiang
背景资料：IL-36在加重银屑病炎症中起关键作用，与寻常型银屑病相比，其在泛发性脓疱型银屑病（GPP）中显著升高。众所周知，阿维A对GPP的治疗效果迅速而显著，但对寻常型银屑病的治疗效果不明显，然而阿维A对GPP的快速治疗机制尚未完全阐明。目的：本研究旨在探讨阿维A是否干扰角质形成细胞中IL-36的表达。我们使用100 ng/mL IL-17 A和/或不同剂量的阿维A（0，0.1，1，10 μ mol/L）处理培养的HaCaT细胞。采用实时荧光定量PCR和ELISA检测IL-36基因和蛋白表达，实时荧光定量PCR和Westem blot检测I kappa B zeta。建立咪喹莫特（IMQ）诱导的银屑病样小鼠模型，评价阿维A胃肠道给药的作用。结果：阿维A可显著下调IL-17 A诱导的HaCaT细胞IL-36 β和IL-36 γ的表达，并在基因和蛋白水平上发挥作用。阿维A对角质形成细胞IL-36表达无明显影响。IMQ +阿维A组皮损程度略有减轻，但免疫组化显示角质形成细胞IL-36 β和IL-36 γ表达较IMQ组明显下降，IL-17 A刺激可诱导HaCaT细胞I κ B zeta表达，阿维A可抑制I κ B zeta表达。阿维A通过下调I κ B ζ抑制角质形成细胞中由IL-17 A刺激诱导的IL-36表达，阿维A显著抑制银屑病样小鼠模型中角质形成细胞表达的IL-36 β和IL-36 γ，这揭示了阿维A对GPP的显著和快速治疗作用的新的可能机制。
Background: IL-36 plays a critical role in aggravating psoriatic inflammation, which is significantly elevated in generalized pustular psoriasis (GPP) compared to psoriasis vulgaris. It is well known that acitretin brings about a rapid and significant effect on the treatment of GPP but not psoriasis vulgaris, whereas the quick therapeutic mechanism of acitretin in GPP has not been fully clarified.Objectives: We conducted this study to investigate whether acitretin interferes IL-36 expression in keratinocytes.Method: We used 100 ng/mL IL-17A and/or various doses of acitretin (0, 0.1, 1, 10 mu mol/L) to treat cultured HaCaT cells. We performed Real-time quantitative PCR and ELISA to detect gene and protein expression of IL-36 cytokines, real-time quantitative PCR and Westem blot to examine I kappa B zeta. Imiquimod (IMQ)-induced psoriasis-like mouse model was established to evaluate effect of gastrointestinal administrated acitretin. Immunohistochemistry was conducted for effect assessment.Results: Acitretin significantly down-regulated expression of IL-36 beta and IL-36 gamma induced by IL-17A stimulation at both gene and protein levels in HaCaT cells. Acitretin alone had no obvious effect on IL-36 expression in keratinocytes. In IMQ + acitretin group, the skin lesion severity was slightly relieved, however, immunohistochemistry showed IL-36 beta and IL-36 gamma expression in keratinocytes significantly declined in comparison with IMQ group, IL-17A stimulation induced significantly I kappa B zeta expression in HaCaT cells, which could be inhibited by acitretin.Conclusion: Acitretin inhibits IL-36 expression induced by IL-17A stimulation in keratinocytes by down-regulating I kappa B zeta, and acitretin significantly inhibits keratinocytes-expressed IL-36 beta and IL-36 gamma in psoriasis-like mouse model, which reveals a new possible mechanism of the notable and quick therapeutic action of acitretin on GPP.