Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy.
Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Br J Pharmacol. 2022 May;179(9):1857-1873. doi: 10.1111/bph.15413. Epub 2021 Mar 21.
Recent biochemical and pharmacological studies have reported that in several tissues and cell types, microsomal PGE synthase (mPGES) and PPAR-γ expression are modulated by a variety of inflammatory factors and stimuli. Considering that very little is known about the biological effects promoted by IL-17 in the context of mPGES-1/PPAR-γ modulation, we sought to investigate the contribution of this unique cytokine on this integrated pathway during the onset of inflammation.
We evaluated effects of PF 9184 (mPGES-1 inhibitor) and troglitazone (PPAR-γ agonist) in vitro, using the mouse macrophage cell line J774A.1. In vivo, the dorsal air pouch model in CD1 mice was used, and inflammatory infiltrates were analysed by flow cytometry. Locally produced cyto-chemokines and PGs were assessed using elisa assays. Western blots were also employed to determine the activity of various enzymes involved in downstream signalling pathways.
PF 9184 and troglitazone, in a time- and dose-dependent manner, modulated leukocyte infiltration, myeloperoxidase activity, and the expression of COX-2/mPGES-1, NF-кB/IкB-α, and mPTGDS-1/PPAR-γ, induced by IL-17. Moreover, both PF 9184 and troglitazone modulated PG (PGE , PGD , and PGJ ) production, the expression of different pro-inflammatory cyto-chemokines, and the recruitment of inflammatory monocytes, in response to IL-17.
Our data suggest that IL-17 may constitute a specific modulator of inflammatory monocytes during later phases of the inflammatory response. The results of this study show, for the first time, that the IL-17/mPGES-1/PPAR-γ pathway could represent a potential therapeutic target for inflammatory-based and immune-mediated diseases.
This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.
最近的生化和药理学研究报告称，在几种组织和细胞类型中，微粒体 PGE 合酶（mPGES）和 PPAR-γ 的表达受多种炎症因子和刺激物调节。鉴于在 mPGES-1/PPAR-γ 调节方面，关于白细胞介素 17（IL-17）促进的生物学效应知之甚少，我们试图研究这种独特的细胞因子在炎症发作时对这一综合途径的贡献。
我们使用小鼠巨噬细胞系 J774A.1 评估了 PF 9184（mPGES-1 抑制剂）和曲格列酮（PPAR-γ 激动剂）的体外作用。在体内，使用 CD1 小鼠的背部气囊中模型，通过流式细胞术分析炎症浸润。使用 ELISA 测定局部产生的细胞因子和 PG。还进行了 Western blot 以确定参与下游信号通路的各种酶的活性。
PF 9184 和曲格列酮以时间和剂量依赖的方式调节白细胞浸润、髓过氧化物酶活性以及 COX-2/mPGES-1、NF-кB/IкB-α 和 mPTGDS-1/PPAR-γ 的表达，由白细胞介素 17 诱导。此外，PF 9184 和曲格列酮调节 PG（PGE、PGD 和 PGJ）的产生、不同促炎细胞因子的表达以及炎症性单核细胞的募集，以响应白细胞介素 17。
我们的数据表明，白细胞介素 17 可能是炎症反应后期炎症性单核细胞的特定调节剂。这项研究的结果首次表明，IL-17/mPGES-1/PPAR-γ 通路可能成为炎症和免疫介导疾病的潜在治疗靶点。
本文是炎症、修复和衰老专题的一部分。要查看本部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.9/issuetoc.
