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  • In conclusion our study has

    2019-09-21

    In conclusion, our study has demonstrated that PGE2 stimulates expression of survivin in hepatocellular carcinoma cells. Although there are 4 subtypes of EP receptors, the EP1 receptor appears to be the predominant receptor that regulates PGE2-induced expression of survivin, mainly through trans-activation of the EGFR/PI3K signaling pathway. These findings suggest that targeting of the PGE2/EP1/survivin signaling pathway may aid in the development of new therapeutic strategies for both the prevention and treatment of this malignant disease.
    Conflict of interest statement
    Acknowledgements We thank Dr. Kathy Mccusker (Merck Frosst Centre for Therapeutic Research, Canada) for providing the pcDNA3 plasmid construct encoding the EP1 receptor. We thank Dr. Tong Wu (University of Pittsburgh School of Medicine, USA) for providing the pcDNA3 plasmid encoding COX-2, and Dr. Bing-Hua Jiang (Nanjing Medical University) for reviewing the manuscript. This study was supported in part by the National Natural Science Foundation of China (30470784, 30871015) and by the Natural Science Foundation of Nanjing Medical University (08NMUZ004).
    Introduction The vascular endothelium forms the barrier between blood circulation and the interstitial space and regulates the exchange of plasma components, adhesion and extravasation of leukocytes, and haemostasis [1]. During inflammatory processes endothelial leakage occurs resulting in plasma extravasation and edema formation [2]. The integrity of the endothelial barrier is tightly regulated by cell-to-cell contacts like adherent and tight junctions between adjacent cells and connection to the HBX 41108 cytoskeleton [1], [3], [4]. Prostanoids and phospholipids such as sphingosin-1-phosphate are involved in the regulation of endothelial barrier [5], [6]. Prostaglandin (PG)E2 is the most abundant prostanoid in humans [7] and exerts a variety of biological functions through four different receptors (EP1–4), which differ in tissue specific gene expression [8]. These receptors activate different signaling pathways: EP1 receptor binding leads to an increase of intracellular Ca levels, assumed of being coupled to a Gαq-protein. EP2 and EP4 receptors induce cyclic AMP (cAMP) production, whereas EP3 receptors couple to a Gαi-protein and inhibit cAMP synthesis [9]. PGE2 is mainly regarded as a potent pro-inflammatory mediator due to its effects on vasodilation, vascular permeability and nociception [10]. However, the role of PGE2 in the regulation of immune responses is more complex. Notably the lung represents a privileged organ with regard to PGE2 actions [11]. In the airways, PGE2 shows an anti-inflammatory mode of action as it was demonstrated to inhibit the release of a number of cytokines and chemokines via activation of the EP4 receptor [10], [11], [12] and inhibition of mast cell-induced bronchoconstriction via the EP2 receptors [13]. However, EP1 and EP3 receptors play a minor role in regulation of inflammatory processes in the lung [12]. PGE2 was shown to enhance the endothelial barrier function of human pulmonary artery endothelial cells via PKA and Epac/Rap activation leading to Rac activation and cytoskeletal remodeling [6]. We recently revealed that PGE2 promotes barrier function in human pulmonary microvascular endothelial cells (HMVEC-L) via EP4 receptor-induced strengthening of the junction and reduces endothelial trafficking of neutrophils [14]. Moreover, we recently demonstrated that PGE2, via activation of the EP4 receptor, also shows barrier promoting effects in vivo in a mouse model of lipopolysaccharide (LPS)-induced acute lung inflammation [15]. In this study we investigated the role 17-phenyl tinor (pt)-PGE2 on endothelial barrier function and the underlying molecular mechanism in HMVEC-Ls as well as in a murine model of LPS-induced acute pulmonary inflammation. We found that 17-pt-PGE2 concentration-dependently enhanced endothelial barrier function, whereas a more specific EP1 receptor agonist ONO DI-004 [16] or the EP3 receptor agonist sulprostone did not mimic this effect. Surprisingly, the effect induced by 17-pt-PGE2 was mediated by the EP4 receptor and not by EP1 or EP3 receptors. Furthermore, we show that 17-pt-PGE2 strengthens the endothelial junctions of HMVEC-Ls and reduces stress fiber formation upon treatment with thrombin. Conversely to our findings in endothelial cells, 17-pt-PGE2 promotes platelet aggregation via EP3 receptors. In a murine model of acute pulmonary inflammation, 17-pt-PGE2 caused a decrease in pulmonary extravasation and a reduction of infiltrating neutrophils, which was mediated by EP4 receptor activation.