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Pharmacology and signaling of prostaglandin receptors: Multiple roles in inflammation and immune modulation

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Prostaglandins are lipid-derived autacoids that modulate many physiological systems including the CNS, cardiovascular, gastrointestinal, genitourinary, endocrine, respiratory, and immune systems. In addition, prostaglandins have been implicated in a broad array of diseases including cancer, inflammation, cardiovascular disease, and hypertension. Prostaglandins exert their effects by activating rhodopsin-like seven transmembrane spanning G protein-coupled receptors (GPCRs). The prostanoid receptor subfamily is comprised of eight members (DP, EP1–4, FP, IP, and TP), and recently, a ninth prostaglandin receptor was identified—the chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2). The precise roles prostaglandin receptors play in physiologic and pathologic settings are determined by multiple factors including cellular context, receptor expression profile, ligand affinity, and differential coupling to signal transduction pathways. This complexity is highlighted by the diverse and often opposing effects of prostaglandins within the immune system. In certain settings, prostaglandins function as pro-inflammatory mediators, but in others, they appear to have anti-inflammatory properties. In this review, we will discuss the pharmacology and signaling of the nine known prostaglandin GPCRs and highlight the specific roles that these receptors play in inflammation and immune modulation.

Introduction

Prostaglandins (PGs) are lipid-derived autacoids generated by sequential metabolism of arachidonic acid by the cyclooxygenase (COX) and prostaglandin synthase enzymes (Fig. 1). Arachidonic acid is a 20-carbon unsaturated fatty acid normally esterified to the sn-2 position of membrane glycerophospholipids. Upon release from the membrane by phospholipase A2, arachidonic acid undergoes oxidation by cyclooxygenase (prostaglandin endoperoxide H synthase; PGHS) to PGG2 followed by reduction to the unstable endoperoxide PGH2 (for a review, see Smith et al., 2000). PGH2 serves as a substrate for the prostaglandin synthase enzymes, which are responsible for the production of the five principal bioactive prostaglandins generated in vivo, PGE2, PGF, PGD2, PGI2 (prostacyclin), and TXA2 (thromboxane). The prostaglandin(s) produced by a given cell largely depends on the expression profile of the individual prostaglandin synthase enzymes. Prostaglandins are ubiquitously produced and act locally in an autacrine or juxtacrine manner to elicit a diverse set of pharmacological effects modulating many physiological systems including the CNS, cardiovascular, gastrointestinal, genitourinary, endocrine, respiratory, and immune systems. In addition, prostaglandin synthesis has been implicated in a broad array of diseases including cancer, inflammation, cardiovascular disease, and hypertension. The physiological importance of prostaglandins is highlighted by the use of the cyclooxygenase-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) in the clinical treatment of various disorders.

Prostaglandins are generally considered to be potent pro-inflammatory mediators, as indicated by the term nonsteroidal anti-inflammatory drugs, used to describe pharmacological agents that block prostaglandin biosynthesis. The cyclooxygenase enzyme exists as two major isozymes that differ in tissue distribution and regulation of expression (Dubois et al., 1998). Although exceptions exist, COX-1 is considered to be constitutively expressed in many tissues while the expression of COX-2 is inducible, particularly in response to inflammatory cytokines and stimuli such as bacterial lipopolysaccharide (LPS). Therefore, prostaglandins produced via COX-1 are usually ascribed a role in physiological homeostasis while those generated via COX-2 are responsible for the inflammatory effects. Traditional NSAIDs, popularly used for their antipyretic, analgesic, and anti-inflammatory properties, inhibit both COX-1 and -2 and are associated with deleterious side effects such as gastrointestinal bleeding due to suppression of both COX isozymes. The more recently developed COX-2-selective inhibitors retain effectiveness in reducing inflammation and pain in rheumatoid and osteoarthritis but have a lower incidence of gastrointestinal adverse events (FitzGerald & Patrono, 2001). Yet, despite the relative clinical effectiveness of COX inhibitors for the treatment of inflammation, emerging evidence now suggests a more complicated picture in which certain prostaglandins may also exert anti-inflammatory effects in some settings.

The physiological effects of prostaglandins are mediated in part by G-protein-coupled prostanoid receptors, a family of rhodopsin-like seven transmembrane spanning receptors (GPCRs). The prostanoid receptor subfamily is comprised of eight members (DP, EP1–4, FP, IP and TP), which are classified according to the prostanoid ligand that each binds with greatest affinity (for a review, see Breyer et al., 2001). Individual prostanoid receptors share ∼20–30% sequence identity with each other and encode specific motifs common only to members of the subfamily. Recently, a ninth prostaglandin receptor was identified—the chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2)—which binds PGD2 (Hirai et al., 2001). Surprisingly, the CRTH2 receptor is more closely related to chemoattractant receptors rather than the other prostanoid receptors (Fig. 2). Prostanoid receptors couple to classic heterotrimeric G protein-mediated signal transduction pathways, and the repertoire of signaling pathways that transduce prostanoid receptor activation into biological effects are complex (Table 1).

The precise roles of prostaglandin receptors in physiologic and pathologic settings are determined by an intricate set of ligand-receptor interactions that depend on multiple factors such as ligand affinity, receptor expression profile, differential coupling to signal transduction pathways, and the cellular context in which the receptor is expressed. Activation of a given prostaglandin receptor by its cognate ligand may elicit varying responses in different cell types and tissues. Moreover, as outlined below, the existence of multiple receptors coupling to different signal transduction pathways for a given prostaglandin (e.g., EP1–4 for PGE2 and DP/CRTH2 for PGD2) allows for potential synergism or antagonism between prostanoid receptor-Scale bar indicates 0.1 amino acid replacement per site mediated effects upon elaboration of a single prostanoid species. It is not surprising, given their structural similarities, that prostaglandins may activate more than one subtype of prostaglandin receptor. Pharmacologic and genetic dissection of prostaglandin receptor function has begun to reveal a complex picture in which prostaglandins serve to both promote and inhibit inflammation (Table 2). In this review, we will discuss the pharmacology and function of the nine known prostaglandin GPCRs and highlight the specific roles that these receptors play in settings of inflammation and immune system activation.

Section snippets

Thromboxane A2 receptor (TP)

Thromboxane A2 (TXA2) has been most extensively characterized for its role in modulating hemodynamics and cardiovascular function. It is a potent mediator of platelet shape change and aggregation, and defective TP receptor signaling has been linked to bleeding disorders (Hirata et al., 1994b, Mitsui et al., 1997). Increased thromboxane synthesis has been linked to cardiovascular diseases including acute myocardial ischemia (Oates et al., 1988) and heart failure (Castellani et al., 1997), and

PGD2 receptors (DP and CRTH2)

PGD2 has long been associated with inflammatory and atopic conditions. In the early 1980s, PGD2 was discovered to be the predominant prostanoid produced by activated mast cells, which initiate IgE-mediated Type I acute allergic responses (Roberts et al., 1980, Lewis et al., 1982). PGD2 is released into the airways following antigen challenge as well as the skin during an acute allergic response (Murray et al., 1986, Barr et al., 1988). PGD2 challenge elicits several hallmarks of allergic asthma

PGE2 receptors (EP1–4)

PGE2 is a major cyclooxygenase product in a number of physiological settings. In the gastrointestinal tract, COX-1-derived PGE2 plays a protective role in maintaining the integrity of the gastric mucosa, and significant gastrointestinal adverse events are associated with prostaglandin inhibition by nonselective NSAIDs (Woo et al., 1986, Warner et al., 1999). Reduced incidence of these complications is observed upon treatment with the PGE2 analogue misoprostol (Silverstein et al., 1995) or use

Prostacyclin receptor (IP)

Prostacyclin (PGI2) is the primary prostaglandin produced by endothelial cells and plays an important role in vascular homeostasis as a result of its potent vasodilatory and antithrombotic effects (Vane & Botting, 1995). Thus, prostacyclin functionally opposes the effects of TXA2 and has been shown to specifically inhibit platelet activation and TXA2-induced vascular proliferation following vascular injury (Cheng et al., 2002). The vasodilatory actions of prostacyclin have enabled its clinical

PGF receptor (FP)

PGF is produced during the menstrual cycle by secretory endometrium (Abel & Baird, 1980) and plays a critical role in mammalian reproduction. Mice deficient in the FP receptor exhibit persistently high progesterone levels during late pregnancy leading to reduced oxytocin receptor expression and impaired parturition (Sugimoto et al., 1997). Fluctuations in PGF production have been linked to a number of reproductive abnormalities including prolonged and painful menstrual bleeding (Smith et

Summary

The diverse actions of prostaglandins are mediated by nine prostanoid-binding GPCRs, which exhibit distinct pharmacology and signaling profiles. These receptors are widely expressed throughout the immune system and function at multiple levels in both the adaptive and innate immune responses. Recent advances in our understanding of the function of the individual receptors have revealed both pro- and anti-inflammatory pathways activated by prostaglandins in physiologic and disease states.

Acknowledgments

We thank Drs. Jason Morrow and Stokes Peebles(VUMC) and Tom Montine (University of Washington) for critical reading of this manuscript. This work was supported by grants from the NIH GM15431 (R.M.B.), DK46205 (R.M.B.), as well as the Vanderbilt-Ingram Cancer Center. A.N.H. is supported by a PhRMA Foundation predoctoral fellowship.

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