Abstract
Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [also D-type prostanoid (DP)] and DP2 (also chemoattractant receptor homologous molecule, expressed on Th2 cells), the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP. Prostanoids can bind to either one or multiple receptors, characteristically have a short half-life in vivo, and are quickly degraded into metabolites with altered affinity and specificity for a given receptor subtype. Prostanoid receptors signal mainly through G proteins and naturally activate signal transduction pathways according to the G protein subtype that they preferentially interact with. This can lead to the activation of sometimes opposing signaling pathways. In addition, prostanoid signaling is often cell-type specific and also the combination of expressed receptors can influence the outcome of the prostanoid impulse. Accordingly, it is assumed that eosinophils and their (patho-)physiological functions are governed by a sensitive prostanoid signaling network. In this review, we specifically focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils. We discuss their significance in allergic and non-allergic diseases and summarize potential targets for drug intervention.
Highlights
Of the known prostanoid receptors, human eosinophils express the prostaglandin D2 (PGD2) receptors DP1 [ D-type prostanoid (DP)] and DP2, the prostaglandin E2 receptors EP2 and EP4, and the prostacyclin (PGI2) receptor IP
We focus on the functions of PGD2, PGE2, and PGI2 and their receptors on eosinophils
It has been observed that IL-5 transgenic mice are protected from airway hyperreactivity, and eosinophils isolated from BAL of OVA-challenged IL-5 transgenic mice do not release superoxides when activated with physiological stimuli [21], which is in sharp contrast to human eosinophils
Summary
A post hoc analysis revealed that the greatest improvement of lung function by timapiprant was observed in patients with active eosinophilia (≥250/μl peripheral blood) and—even more pronounced—in younger patients [90] This applies for the humanized murine IL-5 antibody mepolizumab, which is most effective and only given in asthma patients with severe eosinophilic airway inflammation [91]. A newly developed DP1 antagonist (S-555739, asapiprant) showed improved affinity and bioavailability, and reversed antigen- and PGD2-induced nasal congestion and airway hyperresponsiveness in guinea pigs and sheep, respectively, along with significantly decreased eosinophils and other inflammatory cells in nasal lavage fluid [100].
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