**2. Prostacyclin Signaling and In Vivo Models That Suggest an Inability to Signal through the IP Receptor Augments Allergic Inflammation**

The biological effects of prostacyclin are exerted by signaling through its primary receptor, IP, which is also known as PTGIR in humans. IP is a seven transmembrane spanning G protein-coupled receptor (GPCR) that, when activated, results in increased intracellular cyclic AMP (cAMP) [7,10]. The increase in cAMP levels that result from IP signaling activates protein kinase A (PKA), leading to the phosphorylation of other proteins leading to downstream vasodilatory effects [10]. In addition to prostacyclin signaling through IP, a peroxisome proliferator-activated nuclear receptor (PPAR) may also be stimulated to act as a transcription factor [15]. PPARs exist in multiple isoforms, and while prostacyclin can signal through PPARδ in mice, PPARγ can be activated by prostacyclin analogs [15,16]. The prostacyclin-IP signaling pathway has been the focus of multiple studies using IP knock-out (KO) mice in order to gain a greater understanding of how prostacyclin regulates the allergic airway inflammatory response (Figure 2); however, as described above, IP is not the sole signaling pathway responsible for the effects of prostacyclin.

**Figure 2.** The effects of prostacyclin and its analogs on functions of leukocytes that are important in allergic inflammatory responses. The arrows show how prostacyclin and its analogues regulate specific cell types.

An important tool in understanding how endogenous prostacyclin signaling regulates allergic airway inflammation was the creation of the IP deficient, or knock-out (KO), mouse. Early studies first detailed the effects of the IP receptor signaling in allergic airway inflammation by sensitizing and airway-challenging IP KO mice with ovalbumin to elicit a pulmonary allergen-driven inflammatory response. These studies reported a multi-fold increase in the number of leukocytes in bronchoalveolar lavage fluid (BALF) in IP KO mice relative to their wild-type (WT) counterparts [17,18]. In addition, IP KO mice had a significant increase in the eosinophilic airway and lung inflammation compared to similarly ovalbumin-sensitized and -challenged WT mice. In the ovalbumin model, IP KO mice had more than five times the amount of IL-4 and IL-5 produced in bronchoalveolar lavage fluid (BALF) relative to WT mice [17]. Furthermore, there was also a three-fold increase in the amount of interferon (IFN)-γ produced by splenic CD4+ T cells within the IP KO mice when compared to WT mice [17]. The restraining effect of IP signaling on the production of IFN-γ has since been corroborated by a more recent study that also noted an increase in the level of IFN-γ production from Natural Killer (NK) cells in IP KO mice challenged with house dust mice allergen compared to WT mice [19].
