Tsirvouli Eirini, Ashcroft Felicity, Johansen Berit, Kuiper Martin
Department of Biology, Norwegian University of Science and Technology, 7491 Trondheim, Norway.
iScience. 2021 Nov 15;24(12):103451. doi: 10.1016/j.isci.2021.103451. eCollection 2021 Dec 17.
Psoriasis is a chronic skin disease, in which immune cells and keratinocytes keep each other in a state of inflammation. It is believed that phospholipase A (PLA)-dependent eicosanoid release plays a key role in this. T-helper (Th) 1-derived cytokines are established activators of phospholipases in keratinocytes, whereas Th17-derived cytokines have largely unknown effects. Logical model simulations describing the function of cytokine and eicosanoid signaling networks combined with experimental data suggest that Th17 cytokines stimulate proinflammatory cytokine expression in psoriatic keratinocytes via activation of cPLAα-Prostaglandin E-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLAα inhibition and calcipotriol distinctly regulate expression of key psoriatic genes, possibly offering therapeutic advantage when applied together. Model simulations additionally suggest EP4 and protein kinase cAMP-activated catalytic subunit alpha as drug targets that may restore a normal phenotype. Our work illustrates how the study of complex diseases can benefit from an integrated systems approach.
银屑病是一种慢性皮肤病，其中免疫细胞和角质形成细胞使彼此处于炎症状态。据信，磷脂酶A（PLA）依赖性类花生酸释放在此过程中起关键作用。辅助性T（Th）1衍生的细胞因子是角质形成细胞中磷脂酶的既定激活剂，而Th17衍生的细胞因子的作用在很大程度上尚不清楚。结合实验数据描述细胞因子和类花生酸信号网络功能的逻辑模型模拟表明，Th17细胞因子通过激活cPLAα-前列腺素E-EP4信号传导刺激银屑病角质形成细胞中促炎细胞因子的表达，这可以使用抗银屑病药物卡泊三醇来抑制。cPLAα抑制和卡泊三醇可明显调节银屑病关键基因的表达，联合应用时可能具有治疗优势。模型模拟还表明EP4和蛋白激酶cAMP激活的催化亚基α是可能恢复正常表型的药物靶点。我们的工作说明了复杂疾病研究如何能从综合系统方法中受益。
