Non-cyclic nucleotide EPAC1 activators suppress lipopolysaccharide-regulated gene expression, signalling and intracellular communication in differentiated macrophage-like THP-1 cells

IF 4.4 2区 生物学 Q2 CELL BIOLOGY Cellular signalling Pub Date : 2024-10-03 DOI:10.1016/j.cellsig.2024.111444
Jolanta Wiejak , Fiona A. Murphy , Graeme Barker , Pasquale Maffia , Stephen J. Yarwood
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Abstract

This study explores the anti-inflammatory effects of non-cyclic nucleotide EPAC1 activators, PW0577 and SY007, on lipopolysaccharide (LPS)-induced responses in differentiated THP-1 macrophage-like cells. Both activators were found to selectively activate EPAC1 in THP-1 macrophages, leading to the activation of the key down-stream effector, Rap1. RNA sequencing analysis of LPS-stimulated THP-1 macrophages, revealed that treatment with PW0577 or SY007 significantly modulates gene expression related to fibrosis and inflammation, including the suppression of NLRP3, IL-1β, and caspase 1 protein expression in LPS-stimulated cells. Notably, these effects were independent of p65 NFκB phosphorylation at Serine 536, indicating a distinct mechanism of action. The study further identified a shared influence of both activators on LPS signalling pathways, particularly impacting extracellular matrix (ECM) components and NFκB-regulated genes. Additionally, in a co-culture model involving THP-1 macrophages, vascular smooth muscle cells, and human coronary artery endothelial cells, EPAC1 activators modulated immune-vascular interactions, suggesting a broader role in regulating cellular communication between macrophages and endothelial cells. These findings enhance our understanding of EPAC1's role in inflammation and propose EPAC1 activators as potential therapeutic agents for treating inflammatory and fibrotic conditions through targeted modulation of Rap1 and associated signalling pathways.
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非环核苷酸 EPAC1 激活剂可抑制分化巨噬细胞样 THP-1 细胞中脂多糖调控的基因表达、信号传导和细胞内通讯。
本研究探讨了非环核苷酸 EPAC1 激活剂 PW0577 和 SY007 对分化的 THP-1 巨噬细胞样细胞中脂多糖(LPS)诱导反应的抗炎作用。研究发现,这两种激活剂都能选择性地激活 THP-1 巨噬细胞中的 EPAC1,从而激活关键的下游效应物 Rap1。对LPS刺激的THP-1巨噬细胞进行的RNA测序分析表明,PW0577或SY007能显著调节LPS刺激细胞中与纤维化和炎症相关的基因表达,包括抑制NLRP3、IL-1β和caspase 1蛋白的表达。值得注意的是,这些作用与 p65 NFκB 在丝氨酸 536 处的磷酸化无关,表明其作用机制与众不同。研究进一步确定了两种激活剂对 LPS 信号通路的共同影响,尤其是对细胞外基质(ECM)成分和 NFκB 调控基因的影响。此外,在涉及 THP-1 巨噬细胞、血管平滑肌细胞和人冠状动脉内皮细胞的共培养模型中,EPAC1 激活剂调节了免疫-血管相互作用,表明其在调节巨噬细胞和内皮细胞之间的细胞通讯中发挥着更广泛的作用。这些发现加深了我们对 EPAC1 在炎症中作用的理解,并提出 EPAC1 激活剂是通过靶向调节 Rap1 和相关信号通路治疗炎症和纤维化病症的潜在治疗药物。
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来源期刊
Cellular signalling
Cellular signalling 生物-细胞生物学
CiteScore
8.40
自引率
0.00%
发文量
250
审稿时长
27 days
期刊介绍: Cellular Signalling publishes original research describing fundamental and clinical findings on the mechanisms, actions and structural components of cellular signalling systems in vitro and in vivo. Cellular Signalling aims at full length research papers defining signalling systems ranging from microorganisms to cells, tissues and higher organisms.
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