The ability of a given prostanoid to affect immune cell function depends on its binding to G protein–coupled cell surface receptors. The actions of PGF2α
, and TXA2
are mediated by individual receptors, the FP, IP, and TP receptors, respectively. In contrast, PGD2
activate multiple receptors. PGD2
acts through two receptors, the DP receptor and the recently identified CRTH2 receptor (chemoattractant receptor-homologous molecule expressed on Th2) (8
). There are four subtypes of receptors for PGE2
, termed EP1–EP4, each encoded by a distinct gene. Because the repertoire of receptors expressed by various immune cell populations differs, the function of these cells is modified differently by the prostanoids present in the local environment during an immune response. Table summarizes the expression of prostanoid receptors on immune cells and is based on both pharmacological studies and examination of mRNA.
Prostanoid receptors couple to a range of intracellular signaling pathways that mediate the effects of receptor activation on leukocyte function. The DP, EP2, EP4, IP, and one isoform of the EP3 receptor can couple to Gs and thus increase intracellular cAMP concentration. In T cells and other inflammatory cells, cAMP accumulation is generally associated with inhibition of effector cell functions. EP1, FP, IP, and TP receptors, as well as other EP3 isoforms, couple to Gq, and activation of these receptors leads to increased intracellular calcium levels and thus to immune cell activation. Finally, TP, CRTH2, and yet another EP3 receptor isoform can each couple to Gi, causing cAMP levels to decline while also mobilizing intracellular calcium. As shown in Table , many cells of the immune system express multiple receptors that couple to these apparently opposing pathways. As one example, immature bone marrow–derived mast cells express EP2, EP3, and EP4 receptors. Stimulation of EP2 and EP4 would be expected to inhibit mast cell function while stimulation of the EP3 receptor would increase intracellular calcium and/or inhibit cAMP and thereby promote mast cell degranulation. We still have limited understanding of how these potentially conflicting signals, triggered by the same ligand in the same cell, are integrated and coordinated.
The regulation of the EP2 and EP4 receptors provides additional examples of mechanisms by which cells can modify their responses to prostanoids. Although both receptors bind PGE2
with equal affinity and both are coupled to Gs
, a number of observations indicate that they do not mediate similar cellular functions. Rather, subtle differences between these receptors may provide a means of fine-tuning the organism’s response to extracellular PGE2
. First, while both the EP2 and the EP4 receptors are expressed in most tissues, the level of expression of the EP4 receptor in most cells is higher (9
). However, large increases in EP2 receptor expression are observed under specific physiological conditions. For example, EP2 receptor expression is induced in the uterus just after embryo implantation, and up to fivefold increases in the expression of EP2 have been observed in LPS-stimulated macrophages (9
). In contrast, these macrophages show only a slight increase in EP4 levels, indicating that EP2 and EP4 are also under independent regulation. Moreover, these receptors differ in their rate of desensitization and their ability to bind 15-keto-PGE2
, the primary metabolite of PGE2
; and D. Slipetz, personal communication). The unique functions of these Gs
-coupled receptors are highlighted by the lack of overlap in the phenotypes of EP2- and EP4-deficient mice (11
). Examination of the phenotype of mice deficient in both receptors should determine whether cooperation between these receptors occurs in some physiological settings.
In summary, the impact of prostanoids present during an inflammatory response on both immune effector cells and surrounding stromal cells is determined by the array of receptors the cells express and the intracellular pathways to which they are coupled. Activation of these receptors, even when coupled to similar pathways, might evoke different responses because of different levels of expression (both constitutive and induced), different patterns of desensitization, and differential affinity to metabolites of the primary ligand. Thus, determining the role of prostanoids in a given inflammatory response requires not only knowledge of the lipid mediators present in the lesion, but also the receptor profile on immune cells and the biochemical signaling of these receptors under specific ligand concentrations. Figure , which indicates potential pro- and anti-inflammatory roles of PGE2 and TXA2 in asthma, highlights these complexities.
Figure 1 Potential pro- and anti-inflammatory actions of prostanoids in asthma. (a) Proinflammatory actions of TXA2 and PGE2. Solid red receptors indicate pathways that enhance airway inflammation. TXA2 activates leukocytes and increases airway obstruction by (more ...)