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  • The action of pt PGE as an EP receptor agonist


    The action of 17-pt-PGE2 as an EP1 receptor agonist [34] was demonstrated in several experimental settings, including cancer, neurons, vascular system, kidney and was confirmed by application of EP1 receptor selective antagonists [35], [36], [37], [38], [39], [40], [41]. Receptor binding studies in human and rat EP4 receptor-expressing systems support our findings that 17-pt-PGE2 also can act as an EP4 receptor agonist [42], [43], [44], whilst opposing findings are published for a murine EP4 receptor expressing system [26]. In addition it was shown that 17-pt-PGE2 activates human as well as murine and guinea pig EP3 receptors [26], [34]. With regard to platelets, 17-pt-PGE2 has been described as aggregation-potentiating substance in human platelets [45]. Since it is known that EP3 receptor activation is responsible for enhancing stimulus-induced aggregation in human platelets [46], [47], [48] we investigated the possible involvement of EP3 receptor. It is well established that prostaglandins have a biphasic effect on platelet aggregation, where activation of the EP3 receptor has pro-aggregatory and activation of the EP4 receptor anti-aggregatory effects [23], [24]. Here we show that the pro-aggregatory effect of 17-pt-PGE2 is mediated via EP3 receptor activation. In this model, we did not find an involvement of the EP4 receptor, as even high concentration of 17-pt-PGE2 (10μM) was not capable of inhibiting aggregation induced by collagen. EP1, EP3 and EP4 receptor expression on HMVEC-L was shown recently by flow cytometry [14]. However, only EP4 mRNA expression was previously described in these TMN 355 [49]. Our data obtained with RT-PCR showed EP4 mRNA and very low levels of EP1 mRNA, but no EP2 and EP3 mRNA expression was detectable in HMVEC-L. Although EP1 receptor mRNA was detected, the effects of the purported EP1/EP3 receptor agonist 17-pt-PGE2 on human pulmonary microvascular endothelial cells were exclusively mediated via EP4 receptor activation. In contrast, 17-pt-PGE2 acted on human isolated platelets as an EP3 receptor agonist. The preferential activation of EP4 receptors rather than EP3 receptors can be explained by the lack of EP3 receptor expression and comparatively low amount of EP1 receptors on HMVEC-L.
    Conclusion In conclusion, our results provide evidence that the purported EP1/EP3 receptor agonist 17-pt-PGE2 possesses anti-inflammatory properties, promotes microvascular endothelial barrier function in vitro and further abates neutrophil recruitment and plasma extravasation in a murine model of pulmonary inflammation. Our data suggest that these effects are mediated by EP4 receptor activation and that its mode of action might be tissue and cell specific. We show here for the first time that 17-pt-PGE2 exerts a beneficial effect on pulmonary inflammatory diseases.
    Acknowledgements Grant support: this work was supported by the FWF (DK-MOLIN - W1241, and stand-alone grants P22521 to AH, P25531 to VK and P26185 to RS). AT is a recipient of a DOC Fellowship (24409) of the Austrian Academy of Science at the Institute of Experimental and Clinical Pharmacology.
    Introduction Sensitization of nociceptive primary sensory neurons (nociceptors) plays a crucial role in the development of pathological pain states [8]. Pain mediators enriched in inflamed tissues sensitize the nerve endings of nociceptors. Prostaglandin E2 (PGE2) is well known to sensitize nociceptors and contribute to the genesis of both acute and chronic pain conditions [14]. Through 4 prostaglandin E (EP) receptors (EP1-4) expressed in dorsal root ganglion (DRG) neurons [19], [30], PGE2 directly excites nociceptors by increasing Na+ and Ca++ influx [9], [10], [35] and potentiates other pain mediators such as Adenosine-5′triphosphate [51], bradykinin [39], [43], histamine [28], proton [34], and capsaicin [17], [32]. PGE2 also stimulates or potentiates the release of pain peptide substance P (SP) and calcitonin gene-related peptide (CGRP) from nociceptors [11], [49]. Moreover, we have recently shown that PGE2 contributes to the synthesis of numerous pain mediators in DRG neurons at both gene and protein levels [4], [18], [19], [23], [42].