Mechanisms of allergy and clinical immunologyEndothelial E-type prostanoid 4 receptors promote barrier function and inhibit neutrophil trafficking
Section snippets
Culture of endothelial cells
Human lung microvascular endothelial cells (HMVEC-Ls), human pulmonary artery endothelial cells (HPAECs), and human coronary artery endothelial cells (HCAECs) were purchased from Lonza (Verviers, Belgium). HMVEC-Ls and HCAECs were maintained in EGM-2 MV BulletKit medium (Lonza) with 5% FCS. HPAECs were maintained in EGM-2 BulletKit medium with 2.5% FCS. Endothelial cells were cultivated as previously described.12, 13 For further details on reagents, see the Methods section in this article's
Stimulation of EP4 receptors enhances endothelial barrier function
The selective EP4 agonist ONO AE1-329 (ONO Pharmaceutical, Osaka, Japan) and PGE2 concentration-dependently (10-300 nmol/L) increased endothelial barrier function, which was recorded as electrical impedance, in HMVEC-Ls and, to a lesser extent, in macrovascular HPAECs (Fig 1, A and B). In contrast, the barrier-enhancing effect of S1P (Fig 1, C) was less pronounced in HMVEC-Ls compared with that seen in HPAECs. Specific involvement of the EP4 receptor was demonstrated by preincubating the
Discussion
Our results demonstrate that activation of the PGE2 receptor EP4 increases basal barrier function and prevents barrier dysfunction induced by edemagenic stimuli. We found that the EP4-selective agonist ONO AE1-329 and PGE2 itself concentration-dependently increased the barrier function of human pulmonary microvascular and macrovascular endothelial cells, as indicated by an increase in electrical impedance. The effects of both PGE2 and the EP4 agonist were completely prevented by the selective
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2018, Journal of Allergy and Clinical ImmunologyCitation Excerpt :This suggests an interesting mechanism in which PGE2 requires engagement of both EP2 and EP4 receptors to exert its full inhibitory effect on ILC2 function. In line with our findings, previous studies described anti-inflammatory roles of the Gs protein–coupled EP2 and EP4 receptors.21,25,46,47 Furthermore, PGE2 was shown to control immunologic responses in which such cooperation of EP2 and EP4 receptors was essential, such as in the PGE2-induced inhibition of antigen-specific T-cell responses of human peripheral blood TH2 cells.42
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2016, Vascular PharmacologyCitation Excerpt :Strengthening of vascular barrier function in vitro was shown for PGI2 and PGE2 via cAMP mediated activation of PKA-, Epac/Rap1- and Tiam1/Vav2-dependent pathways of Rac1 activation [6]. Recently, we demonstrated that EP4 receptor activation is responsible for the barrier-enhancing effect of PGE2, which was independent of cAMP/PKA, PKC, NO or Rac signaling but was mediated by cytoskeletal rearrangements [14]. This is in line with our findings, as 17-pt-PGE2 did not induce cAMP synthesis in HMVEC-L.
V.K., A.Ü., and S.P. were funded by the PhD Program Molecular Medicine of the Medical University of Graz. This work was supported by the Start Funding Program of the Medical University of Graz (ASO109000101 to V.K.), the Austrian Science Fund FWF (grants P22521 to A.H., P21004 to G.M., and SFB Lipotox project 3007 to W.S.), and Jubiläumsfonds of the Austrian National Bank (14263 to A.H. and 13487 to R.S.).
Disclosure of potential conflict of interest: A. Heinemann has received one or more payments for lecturing from AstraZeneca AB (Sweden), is a Principal Investigator for the Austria Science Funds (FWF) and for Jubilaümfonds of the Austrian National Bank (OeNB), and has received research funding from AstraZeneca AB (Sweden) and from Alimrall SA (Spain). The rest of the authors declare that they have no relevant conflicts of interest.