Woolcock Emphysema Centre, Woolcock Institute of Medical Research, University of Sydney, Sydney, NSW, Australia.
School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia.
Inflamm Res. 2019 May;68(5):369-377. doi: 10.1007/s00011-019-01224-0. Epub 2019 Mar 9.
Tristetraprolin (TTP) is an anti-inflammatory molecule known to post-transcriptionally regulate cytokine production and is, therefore, an attractive drug target for chronic respiratory diseases driven by inflammation, such as asthma and chronic obstructive pulmonary disease. Our recent in vitro studies in primary human airway smooth (ASM) cells have confirmed the essential anti-inflammatory role played by TTP as a critical partner in a cytokine regulatory network. However, several unanswered questions remain. While prior in vitro studies have suggested that TTP is regulated in a cAMP-mediated manner, raising the possibility that this may be one of the ways in which β-agonists achieve beneficial effects beyond bronchodilation, the impact of β-agonists on ASM cells is unknown. Furthermore, the effect of prostaglandin E (PGE) on TTP expression in ASM cells has not been reported. We address this herein and reveal, for the first time, that TTP is not regulated by cAMP-activating agents nor following treatment with long-acting β-agonists. However, PGE does induce TTP mRNA expression and protein upregulation in ASM cells. Although the underlying mechanism of action remains undefined, we can confirm that PGE-induced TTP upregulation is not mediated via cAMP, or EP/EP receptor activation, and occurred in a manner independent of the p38 MAPK-mediated pathway. Taken together, these data confirm that β-agonists do not upregulate TTP in human ASM cells and indicate that another way in which PGE may achieve beneficial effects in asthma and COPD may be via upregulation of the master controller of inflammation-TTP.
Tristetraprolin (TTP) 是一种抗炎分子，已知可在后转录水平上调节细胞因子的产生，因此是由炎症驱动的慢性呼吸道疾病（如哮喘和慢性阻塞性肺疾病）的有吸引力的药物靶点。我们最近在原代人呼吸道平滑肌 (ASM) 细胞中的体外研究证实了 TTP 作为细胞因子调节网络中的关键伙伴所发挥的重要抗炎作用。然而，仍有几个悬而未决的问题。虽然先前的体外研究表明 TTP 受 cAMP 调节，这增加了 TTP 可能是β-激动剂除了支气管扩张之外实现有益效果的方式之一的可能性，但β-激动剂对 ASM 细胞的影响尚不清楚。此外，前列腺素 E (PGE) 对 ASM 细胞中 TTP 表达的影响尚未报道。我们在此解决了这个问题，并首次揭示 TTP 不受 cAMP 激活剂调节，也不受长效β-激动剂治疗的调节。然而，PGE 确实会诱导 ASM 细胞中 TTP mRNA 表达和蛋白上调。虽然作用机制尚不清楚，但我们可以确认 PGE 诱导的 TTP 上调不是通过 cAMP 或 EP/EP 受体激活介导的，而是以一种独立于 p38 MAPK 介导途径的方式发生的。总之，这些数据证实β-激动剂不会上调人 ASM 细胞中的 TTP，并表明 PGE 可能在哮喘和 COPD 中实现有益效果的另一种方式可能是通过上调炎症的主控制器-TTP。
