Mori Hiroki, Arita Kojo, Yamaguchi Takayuki, Hirai Midori, Kurebayashi Yoichi
Department of Integrated Drug Discovery Sciences, Kobe University Graduate School of Medicine, Kobe, Japan.
Biological/Pharmacological Research Laboratories, Central Pharmaceutical Research Institute, Japan Tobacco Inc., Takatsuki, Japan.
Kobe J Med Sci. 2016 Sep 9;62(4):E79-E88.
Psoriasis is a chronic inflammatory skin disease mediated by dysregulated auto-reactive immune system. In this study, in order to confirm and further extend the pharmacological basis of topical steroids in psoriasis therapy, we investigated the effect of betamethasone ointment on imiquimod (IMQ)-induced skin inflammation in mice. In BALB/c mice, topical IMQ at the dose of 250 µg each on both sides of the ear induced marked psoriasis-like skin inflammation within 5 days. The same dose of IMQ produced only slight to moderate skin inflammation even on Day 7 in CB-17 scid mice. IMQ-induced skin inflammation was associated with increased levels of mRNA transcripts expression of signature cytokines of T helper (Th)1/Th17 cells, i.e., interferon-γ, interleukin (IL)-17 and IL-22 on Day 5. In addition, levels of mRNA expression of the markers of keratinocytes, i.e., IL-1β, S100A8, and S100A9, were dramatically elevated in IMQ-treated mice. The IMQ-induced changes in cytokine expression were significantly suppressed by topical treatment with betamethasone ointment. IMQ failed to produce significant changes in the mRNA levels of tumor necrosis factor-α as a marker of macrophages and NK1.2 as a marker of natural killer cells and natural killer T cells. In contrast, mRNA level of a Th2 cytokine IL-13 was significantly decreased by IMQ treatment and further suppressed by betamethasone. These findings provide the first pharmacological evidence that the topical application of betamethasone prevents IMQ-induced psoriasis-like skin inflammation in mice by inhibiting gene expressions of various cytokines related to Th1 cells, Th17 cells and keratinocytes.
银屑病是一种由失调的自身反应性免疫系统介导的慢性炎症性皮肤病。在本研究中，为了证实并进一步拓展局部用糖皮质激素治疗银屑病的药理学依据，我们研究了倍他米松软膏对咪喹莫特（IMQ）诱导的小鼠皮肤炎症的影响。在BALB/c小鼠中，双侧耳部各局部涂抹250μg的IMQ，5天内即可诱导出明显的银屑病样皮肤炎症。相同剂量的IMQ在CB-17重度联合免疫缺陷小鼠中，即使在第7天也仅产生轻微至中度的皮肤炎症。IMQ诱导的皮肤炎症与第5天辅助性T细胞（Th）1/Th17细胞标志性细胞因子，即干扰素-γ、白细胞介素（IL）-17和IL-22的mRNA转录本表达水平升高有关。此外，IMQ处理的小鼠中角质形成细胞标志物，即IL-1β、S100A8和S100A9的mRNA表达水平显著升高。倍他米松软膏局部治疗可显著抑制IMQ诱导的细胞因子表达变化。IMQ未能使作为巨噬细胞标志物的肿瘤坏死因子-α和作为自然杀伤细胞及自然杀伤T细胞标志物的NK1.2的mRNA水平产生显著变化。相反，IMQ处理可使Th2细胞因子IL-13的mRNA水平显著降低，倍他米松进一步抑制了该水平。这些发现提供了首个药理学证据，即局部应用倍他米松可通过抑制与Th1细胞、Th17细胞和角质形成细胞相关的各种细胞因子的基因表达，预防IMQ诱导的小鼠银屑病样皮肤炎症。
