Prabhala Pavan, Bunge Kristin, Ge Qi, Ammit Alaina J
Faculty of Pharmacy, University of Sydney, Sydney, New South Wales, Australia.
Woolcock Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.
J Cell Physiol. 2016 Oct;231(10):2153-8. doi: 10.1002/jcp.25327. Epub 2016 Feb 16.
Exaggerated cytokine secretion drives pathogenesis of a number of chronic inflammatory diseases, including asthma. Anti-inflammatory pharmacotherapies, including corticosteroids, are front-line therapies and although they have proven clinical utility, the molecular mechanisms responsible for their actions are not fully understood. The corticosteroid-inducible gene, mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1, DUSP1) has emerged as a key molecule responsible for the repressive effects of steroids. MKP-1 is known to deactivate p38 MAPK phosphorylation and can control the expression and activity of the mRNA destabilizing protein-tristetraprolin (TTP). But whether corticosteroid-induced MKP-1 acts via p38 MAPK-mediated modulation of TTP function in a pivotal airway cell type, airway smooth muscle (ASM), was unknown. While pretreatment of ASM cells with the corticosteroid dexamethasone (preventative protocol) is known to reduce ASM synthetic function in vitro, the impact of adding dexamethasone after stimulation (therapeutic protocol) had not been explored. Whether dexamethasone modulates TTP in a p38 MAPK-dependent manner in this cell type was also unknown. We address this herein and utilize an in vitro model of asthmatic inflammation where ASM cells were stimulated with the pro-asthmatic cytokine tumor necrosis factor (TNF) and the impact of adding dexamethasone 1 h after stimulation assessed. IL-6 mRNA expression and protein secretion was significantly repressed by dexamethasone acting in a temporally distinct manner to increase MKP-1, deactivate p38 MAPK, and modulate TTP phosphorylation status. In this way, dexamethasone-induced MKP-1 acts via p38 MAPK to switch on the mRNA destabilizing function of TTP to repress pro-inflammatory cytokine secretion from ASM cells. J. Cell. Physiol. 231: 2153-2158, 2016. © 2016 Wiley Periodicals, Inc.
细胞因子分泌过度会引发包括哮喘在内的多种慢性炎症性疾病的发病机制。包括皮质类固醇在内的抗炎药物疗法是一线治疗方法，尽管它们已被证明具有临床效用，但其作用的分子机制尚未完全明确。皮质类固醇诱导基因——丝裂原活化蛋白激酶（MAPK）磷酸酶1（MKP-1，DUSP1）已成为负责类固醇抑制作用的关键分子。已知MKP-1可使p38 MAPK磷酸化失活，并能控制mRNA去稳定蛋白——锌指蛋白（TTP）的表达和活性。但皮质类固醇诱导的MKP-1是否通过p38 MAPK介导的TTP功能调节作用于关键气道细胞类型——气道平滑肌（ASM）尚不清楚。虽然已知用皮质类固醇地塞米松预处理ASM细胞（预防方案）可在体外降低ASM合成功能，但尚未探究刺激后添加地塞米松（治疗方案）的影响。地塞米松是否以p38 MAPK依赖性方式调节该细胞类型中的TTP也不清楚。我们在此解决了这一问题，并利用哮喘炎症的体外模型，其中用促哮喘细胞因子肿瘤坏死因子（TNF）刺激ASM细胞，并评估刺激后1小时添加地塞米松的影响。地塞米松以时间上不同的方式发挥作用，增加MKP-1、使p38 MAPK失活并调节TTP磷酸化状态，从而显著抑制白细胞介素-6 mRNA表达和蛋白分泌。通过这种方式，地塞米松诱导的MKP-1通过p38 MAPK发挥作用，开启TTP的mRNA去稳定功能，以抑制ASM细胞分泌促炎细胞因子。《细胞生理学杂志》2016年第231卷：2153 - 2158页。©2016威利期刊公司
