Function of prostanoid receptors: studies on knockout mice

Prostaglandins & other Lipid Mediators 68–69 (2002) 557–573

Function of prostanoid receptors: studies on knockout mice Takuya Kobayashi, Shuh Narumiya∗ Department of Pharmacology, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

Abstract Prostanoids consisting of the prostaglandins (PGs) and the thromboxanes (TXs) are the cyclooxygenase metabolites of arachidonic acid. They exert a range of actions mediated by their respective receptors expressed in the target cells. The receptors include the DP, EP, FP, IP and TP receptors for PGD, PGE, PGF, PGI and TXA, respectively. Furthermore, EP is subdivided into four subtypes, EP1, EP2, EP3 and EP4, which are encoded by different genes and differ in their responses to various agonists and antagonists. Recent developments in the molecular biology of the prostanoid receptors have enabled the investigation of physiological roles of each receptor by disruption of the respective gene. At this point, all the eight types and subtypes of the prostanoid receptors have been individually knocked out in mice, and various phenotypes have been reported for each strain. Here, we review the findings obtained in these studies. The results from these knockout mice studies may be useful in the development of novel therapeutics that can selectively manipulate actions mediated by each receptor. © 2002 Elsevier Science Inc. All rights reserved. Keywords: Prostanoid receptors; Prostaglandins; Knockout mice

1. Introduction Prostanoids consisting of the prostaglandins (PGs) and thromboxanes (TXs) are synthesized via the cyclooxygenase (COX) pathway in a variety of cells in response to various physiological and pathophysiological stimuli. Prostanoids are quickly released outside the cells and act as autocrine or paracrine mediators in the vicinity of their sites of production to maintain local homeostasis. Prostanoids exert a wide variety of actions in the body, which are mediated by specific receptors on plasma membranes. The receptors include the DP, EP, FP, IP and TP receptors that preferentially respond to PGD2 , PGE2 , PGF2␣ , PGI2 , and TXA2 , respectively. Furthermore, EP is subdivided into four subtypes, EP1, EP2, EP3 and ∗

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Table 1 Major phenotypes of prostanoid receptor knockout mice Genotypes

Phenotypes

DP (−/−) EP1 (−/−)

Decreased allergic responses in ovalbumin-induced bronchial asthma Decreased aberrant foci formation to azoxymethane

EP2 (−/−)

Impaired ovulation and fertilization Salt-sensitive hypertension Vasopressor or impaired vasodepressor response to intravenous PGE2 Loss of bronchodilation with PGE2 Impaired osteoclastogenesis in vitro

EP3 (−/−)

Impaired febrile response to pyrogens Impaired duodenal bicarbonate secretion and mucosal integrity Enhanced vasodepressor response to intravenous infusion of PGE2 Disappearance of indomethacin-sensitive urine diluting function

EP4 (−/−)

Patent ductus arteriosus Impaired vasodepressor response to intravenous infusion of PGE2 Decreased inflammation-dependent bone resorption

FP (−/−)

Loss of parturition

IP (−/−)

Thrombotic tendency Decreased inflammatory swelling Decreased acetic acid writhing

TP (−/−)

Bleeding tendency and resistance to thromboembolism

EP4. The physiological roles of prostanoids have been investigated by examining the effects of aspirin-like drugs that inhibit prostanoid production and by analyzing the in vitro and in vivo actions of each prostanoid added exogenously. However, it is not necessarily clear as to which type of prostanoid receptor is involved in each process. Neither is it clear how critical the actions of prostanoids are in each process. Recent progress in targeted disruption of the receptor genes has enabled us to examine the physiological importance of the action of prostanoids mediated by each prostanoid receptor. Phenotypes observed in mice deficient in each prostanoid receptor have been reported. In this review, we summarize the findings from studies of these knockout mice and discuss their significance in elucidating physiological and pathophysiological roles of prostanoid receptors (Table 1).

2. Receptors mediating central nervous system actions 2.1. Fever generation Fever is a representative component of the acute phase response to immunological challenge and is elicited by cellular components of infectious organisms, such as LPS, as well as by noninfectious inflammatory insults. Both infectious and noninfectious insults stimulate the production of cytokines that work as endogenous pyrogens. These cytokines, including IL-1, IL-6, TNF-␣, IFN-␣, and IFN-␥ transmit a signal to the preoptic area (POA),

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which then stimulates the neural pathways that raise body temperature [1,2]. Fever can be suppressed by nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin and indomethacin, indicating that PGs are important in fever generation. Ushikubi et al. [3] used mice lacking each subtype of the PGE receptor, EP1, EP2, EP3 and EP4, and examined their febrile responses to PGE2 , IL-1␤, and LPS. They found that the EP3 receptor-deficient mice failed to show febrile responses to all of these stimuli. This study has thus clearly demonstrated that PGE2 mediates fever generation in response to both exogenous and endogenous pyrogens by acting on the EP3 receptor. Then, where in the brain is PGE2 formed, and where does it act? Because electrolytic lesions placed within the organum vasculosa lamina terminalis (OVLT) altered the febrile response to endogenous pyrogens, involvement of the OVLT, a circumventricular organ, in fever production was suggested [4,5]. The OVLT is located in the midline of the POA and is poor in a blood-brain barrier; thus it is suitable as the site for circulating cytokines to act to produce PGE2 for fever production. Indeed, intravenous administration of LPS induces COX-2 expression in endothelial cells in the OVLT [6]. It has been reported that COX-2-deficient mice also showed impaired febrile responses, as observed in EP3-deficient mice [7]. Furthermore, Ek [8] reported results from a dual in situ hybridization technique that in rat brain almost all vascular cells expressing mRNA for COX-2 showed an IL-1-induced upregulation of microsomal form of PGE synthase (mPGES) mRNA, and most of the cells expressing mPGES mRNA also co-expressed mRNA encoding the type-1 receptor for IL-1. Yamagata et al. [9] cloned the rat glutathione-dependent mPGES, and examined its induction in the rat brain after intraperitoneal injection of LPS. In Northern blot analysis, mPGES mRNA was weakly expressed in the brain under the normal conditions but was markedly induced between 2 and 4 h after the LPS injection. An immunohistochemical study demonstrated that mPGES and COX-2 were colocalized in the perinuclear region of brain endothelial cells. These results demonstrate that brain endothelial cells play an essential role in PGE2 production during fever by expressing COX-2 and mPGES. This is also consistent with the findings that the OVLT is the most sensitive area of the brain in producing fever in response to microinjection of PGE2 [10,11] and that neurons in the OVLT are sensitive to thermal and PGE2 stimuli [12]. Matsumura and co-workers [13,14] used quantitative autoradiography to determine [3 H]PGE2 binding sites in the rat preoptic-hypothalamic area and in the whole rat brain. They found the highest density of binding in the regions of the anterior wall of the third ventricle surrounding the OVLT and the nucleus tractus solitarius (NTS). Two thalamic nuclei (the paraventricular and anteroventral nuclei) and the dorsal parabrachial nucleus also contained a high density of [3 H]PGE2 binding sites. These studies, however, could not establish which subtypes of the PGE receptor mediate this effect. Sugimoto et al. [15] clarified this point by performing in situ hybridization analyses on expression of PGE receptor subtypes in the mouse brain. They found that although the mRNA for the EP3 receptor was widely distributed in the brain, it was particularly abundant in the regions surrounding the OVLT. Furthermore, Nakamura et al. recently confirmed the expression of rat EP3 receptor protein in the cell bodies of these neurons with a distribution pattern similar to that of EP3 mRNA [16] Scammell et al. [10] studied the neuronal pathways activated in association with PGE2 -mediated fever by examining Fos induction after the microinjection of PGE2 into the ventromedial preoptic area (VMPO). They found Fos induction in the VMPO and the autonomic regulatory and corticotropin-releasing hormone

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(CRH)-producing subdivisions of the paraventricular nucleus of the hypothalamus (PVH). The PVH projects directly to preganglionic sympathetic and parasympathetic neurons, as well as to sympathetic premotor sites in the parabrachial nucleus, ventrolateral medulla (VLM), and NTS. Thus, it was suggested that the VMPO, though its connections with the PVH, contributes to increased sympathetic activity and redistributes the blood flow required for the production of fever. 2.2. Sleep PGD2 is a potent endogenous sleep promoting substance in rats and other mammals including humans [17]. PGD2 infused into the subarachnoid space underlying the rostral basal forebrain was effective in inducing sleep but was not effective when infused into most parts of the brain parenchyma of rats [18]. To clarify the involvement of DP in PGD2 -induced sleep, Mizoguchi et al. [19] infused PGD2 into the lateral ventricle of wild-type and DP-deficient mice at flow rates of 10 and 50 pmol/min for 6 h starting from 8 pm and determined the amounts of nonrapid eye movement (NREM) and rapid eye movement (REM) sleep. In wild-type mice, the PGD2 infusion at a flow rate of 10 pmol/min significantly increased NREM sleep even 2 h after the start of infusion. The total amount of NREM sleep during the PGD2 infusion (10 pmol/min) was about two-fold higher than that observed with the infusion of vehicle. A higher dose of PGD2 (50 pmol/min) induced a greater degree of and more prolonged NREM sleep than the lower dose. REM sleep was slightly increased during the PGD2 infusion only with 50 pmol/min. In DP-deficient mice, however, the amounts of NREM and REM sleep were unchanged by PGD2 infusion even at a flow rate of 50 pmol/min. These results clearly demonstrate that PGD2 predominantly increased NREM sleep in wild-type mice and that DP receptors are crucially involved in the PGD2 -induced NREM sleep. It is known that the amount of PGD2 -induced sleep is reduced by pretreatment with the specific adenosine A2A receptor antagonist, KF17837, in a dose-dependent manner [20]. Moreover, administration of the selective adenosine A2A receptor agonist, CGS21680, into the subarachnoid space induced sleep [21], suggesting that PGD2 -induced sleep is mediated by adenosine through the adenosine A2A receptor system. Consistently, Mizoguchi et al. [19] also demonstrated using DP-deficient mice that DP mediates an increase in the extracellular adenosine content in the subarachnoid space of the rostral basal forebrain after PGD2 infusion.

3. Receptors mediating inflammation and pain Local reddening, heat generation, swelling, and pain are classic signs of acute inflammation. Each of these symptoms except pain is caused by increased blood flow and vascular permeability with resultant edema. Previous studies suggested that PGs are primarily involved in vasodilation in the inflammatory process and synergize with other mediators such as histamine and bradykinin to cause an increase in vascular permeability and edema. These studies also showed that PGE2 and PGI2 are the potent prostanoids in causing these effects and that both these PGs are present at high concentrations at sites of inflammation [22]. Murata et al. [23] used IP-deficient mice to test the role of PGI2 in inflammatory swelling. They

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employed carageenan-induced paw swelling as a model. In this model, swelling increased in a time-dependent manner up to 6 h after injection and was decreased by about 50% upon treatment with indomethacin. IP-deficient mice developed swelling only to a level comparable to that observed in indomethacin-treated wild-type mice, and indomethacin treatment of IP-deficient animals did not induce a further decrease in swelling. On the other hand, PGE2 injected intradermally could synergize with bradykinin to induce increased vascular permeability in both wild-type and IP-deficient mice. These results indicate that PGI2 and IP receptor work as the principal PG system mediating vascular changes in this model of inflammation. Whether PGI2 and the IP receptor play a dominant role in any type of inflammation remains to be seen. An alternative and more likely possibility is that this system and the PGE2 and EP receptor system are utilized in a context-dependent manner, i.e. one dependent on the stimulus, site, and time of inflammation. This point will likely be clarified by comparing responses in IP-deficient mice with those in mice deficient in each subtype of the EP receptors in various inflammation models. The role of prostaglandins in inflammatory pain is also well accepted. This is partly due to the antinociceptive effects of aspirin-like drugs, and also because of documentation in various model systems that PG added exogenously are able to induce hyperalgesia, an increased sensitivity to a painful stimulus, or allodynia, a pain response to a usually nonpainful stimulus. These studies using exogenous PGs showed that PGE2 , PGE1 , and PGI2 exert stronger effects than the other types of PG, indicating the involvement of EP or IP receptors in inducing inflammatory pain [24]. The main site of hyperalgesic prostanoid action lies in the periphery where prostaglandins are believed to sensitize the free ends of sensory neurons. The primary sensory afferents have their cell bodies in the dorsal root ganglion (DRG), and several types of prostanoid receptor mRNAs, including those of IP, EP1, EP3, and EP4, were found in neurons in the ganglion [15], suggesting their possible involvement. Some IP-expressing neurons also express preprotachykinin A mRNA, indicating a role of IP in nociception via substance P-containing afferents [25]. Murata et al. [23] used IP receptor-deficient mice to address this issue. The IP-deficient mice did not show any alteration in their nociceptive reflexes examined by hot plate and tail flick tests, indicating that PGI2 is not involved in nociceptive neurotransmission at the spinal and supraspinal levels. On the other hand, when these mice were subjected to the acetic acid-induced writhing test, they showed markedly decreased responses compared with control wild-type mice, and their responses were as low as those observed in control mice treated with indomethacin. Additionally, both PGE2 and PGI2 injected intraperitoneally-induced modest writhing responses in wild-type mice, whereas IP-deficient mice showed responses only to PGE2 . These results indicate that the hyperalgesic response in this model is evoked by endogenous PGI2 acting on the IP receptor in the peripheral end of nociceptive afferents. This study, together with other reports that PGI2 or its agonists are more effective in eliciting nociception in several model systems, has led to the proposal that IP has a key role in facilitating the sensation of pain [24]. Recently, however, we found that the receptors other than IP can also amplify pain sensations in a context-dependent manner. Ueno et al. [26] pretreated EP1−/− , EP2−/− , EP3−/− , EP4−/− , IP−/− and wild-type mice with LPS and then examined their hyperalgesic responses. Whereas EP1−/− , EP2−/− and EP4−/− mice showed a similar enhanced writhing response as the wild-type mice, IP−/− and EP3−/− mice showed significant reductions in writhing. These results demonstrated that the

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nociception of the writhing response in nontreated mice is mediated mainly by the IP receptor and the perception of enhanced pain in LPS-pretreated mice can be mediated by both IP and EP3 receptors. Probably consistent with this finding, two groups reported that a neutralizing monoclonal antibody against PGE2 inhibits phenylbenzoquinone-induced writhing in mice and carageenan-induced paw hyperalgesia in rats to the same extent as indomethacin [27,28]. In addition to these hyperalgesic actions in the periphery, recent studies demonstrated that PGs have additional sites of action both in spinal cord and in the brain to elicit hyperalgesia. Malmberg and Yaksh [29] showed that the spinal injection of NSAIDs into rats inhibits thermal hyperalgesia induced by the activation of spinal glutamate and substance P receptors. Oka et al. [30] reported that the intracerebroventricular injection of PGE2 induces thermal hyperalgesia in rats. It should be determined therefore whether any of the EP and IP receptors expressed in dorsal ganglion neurons have a modulatory role in sensory neurotransmission in the spinal cord. Indeed, an autoradiographic study detected a high density of [3 H]PGE2 binding sites in the dorsal horn that was abolished by dorsal rhizotomy [31]. In addition to hyperalgesic actions, PGs in the spinal cord are also reported to be involved in elicitation of allodynia. To characterize the PGE receptor subtype(s) involved in PGE2 -induced mechanical allodynia, Minami examined whether PGE2 could induce allodynia in the EP1- and EP3-deficient mice [32]. Intrathecal (i.t.) administration of PGE2 (500 ng/kg) induced allodynia over the 50-min experimental period in the wild-type and the EP3-deficient mice, but not in the EP1-deficient mice. These results clearly demonstrate that the EP1 receptor is involved in the PGE2 -induced allodynia.

4. Receptors mediating allergy and immunity Allergic asthma is caused by the aberrant expansion of Th cells in the lung that produce Th2-cytokines, and is characterized by the infiltration of eosinophils and bronchial hyperreactivity [33,34]. This disease is often triggered by mast cells activated by an immunoglobulin (Ig) E-mediated allergic challenge. Activated mast cells release various chemical mediators. PGD2 is the major prostanoid produced by these cells in response to antigen challenge [35]. PGD2 is released in large amounts during asthmatic attacks in humans, and it has been proposed as a marker of mast cell activation [36]. However, the pathological significance of PGD2 in allergic asthma remains unclear. Matsuoka et al. [37] recently focused on the specific role of PGD2 in this response by using DP-deficient mice. They introduced DP-deficient mice into the ovalbumin (OVA)-induced asthma model in which PGD2 is generated in response to an antigen challenge. Sensitization and aerosol challenge of DP-deficient mice with OVA-induced increases in the serum concentration of IgE, similar to that found in wild-type mice. However, DP-deficient mice did not develop asthmatic responses in this model; OVA-challenged DP-deficient mice showed decreased concentrations of Th2-cytokines and a reduced extent of lymphocyte accumulation and eosinophil infiltration in the lung compared to the wild-type animals subjected to this model. Interestingly, DP expression was seen in bronchiolar and alveolar epithelial cells only in antigen-challenged mice but not in immunized mice before the antigen challenge. From these results, the authors proposed that PGD2 produced in response to allergic challenge acts at DP receptors

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in the lung to recruit lymphocytes to the site of challenge. Thus, it is apparent that PGD2 functions as a mast cell-derived mediator to trigger asthmatic responses. The above findings suggest that NSAIDs should have beneficial effects on asthma patients, if PGD2 is the only PG working in this disease. However, there is a subset of patients with asthma in whom aspirin precipitates asthmatic attacks. This is a distinct clinical syndrome, called aspirin-induced asthma (AIA) [38]. The existence of such a syndrome suggests that PGs other than PGD2 work to suppress the asthmatic attack. Gavaett et al. [39] reported that both COX-1-deficient and COX-2-deficient mice showed enhanced allergic lung responses in a similar asthmatic model; this study highlighted the beneficial aspects of prostanoids in this model. The authors discussed the possibility that some of these increased responses derive from increased biosynthesis of leukotrienes in COX-1-deficient mice. However, since the increased allergic responses seen with both types of knockout mice could not be entirely explained by this hypothesis, the authors concluded that both COX-1 and COX-2 products limit allergic lung inflammation. A most likely explanation for the increased responses in both types of COX-deficient mice is the loss of the anti-asthmatic effects of PGE2 , but the receptor mediating this effect has not been identified. PGE2 has been reported to attenuate some acute inflammatory responses initiated by mast cell degranulation. Raud et al. [40] have shown that indomethacin markedly potentiates antigen-induced plasma protein extravasation, leukocyte accumulation and histamine release in sensitized hamsters. PGE2 completely reversed the indomethacin-induced potentiation of plasma extravasation and also effectively reversed the number of emigrating leukocytes after indomethacin treatment. Histamine release was reduced by almost 60% in the presence of PGE2 . The identity of the EP receptor mediating this action remains to be clarified. PGs are likely to play physiological roles in the regulation of immunity and allergy. TP and IP receptors were found to be highly expressed by immature and mature thymocytes, respectively [25,41]. Furthermore, a TXA2 mimetic was shown to induce apoptosis of immature thymocytes in vitro, leading to the suggestion that the TXA2 and TP system may have an antigen-dependent immunomodulatory role [41]. In this respect, it would be interesting to see whether there are any abnormalities in the immunities of TP- and IP-deficient mice. Compared with TXA2 and PGI2 , E type PGs have long attracted the attention of immunologists because of the potent immunosuppressive actions of PGE derivatives. For example, PGE2 induces apoptosis of thymocytes and inhibits some T cell functions such as production of IL-2 [42]. PGE2 has also been shown to activate the Th2 subset of T cells, while suppressing the Th-1 subset [43]. Moreover, it has been reported that PGE2 acts on the EP2 and/or EP4 receptor of B cells and synergizes with LPS or a Th2 cytokine, IL-4, to facilitate IgE production [44]. These findings led to the proposal that PGE2 may work as a switch for Th2-mediated allergic responses. Whether such a mechanism operates under physiological conditions must be tested in mice deficient in each of the EP receptors. PGs have also been known to regulate the production or release of proinflammatory cytokines. Recently, Shinomiya et al. [45] collected peritoneal macrophages from wild type, IP−/− , EP2−/− , and EP4−/− mice and examined the effects of PGE2 or the PGI2 analogue carbacyclin on the production of TNF␣ and IL-10 by these macrophages stimulated with zymosan. The addition of PGE2 or carbacyclin to wild type macrophages reduced the TNF␣ production to one-half, whereas IL-10 production increased several fold. And a phosphodiesterase inhibitor and dibutyryl cAMP dose-dependently decreased TNF␣ and increased

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IL-10. Macrophages collected from IP-deficient mice showed a down-regulation of TNF␣ production and an up-regulation of IL-10 production only in response to EP2 and EP4 agonists or PGE2 , but not to carbacyclin. Conversely, EP2−/− and EP4−/− macrophages lacked the response to EP2 and EP4 agonists, but not to PGE2 or carbacyclin. These results demonstrate that PGE2 and PGI2 regulate production of proinflammatory (TNF␣) and anti-inflammatory (IL-10) cytokines redundantly through EP2, EP4 and IP receptors by causing an increase in cAMP.

5. Receptors mediating vascular homeostasis 5.1. Thrombosis and hemostasis Most PGs elicit contractile and/or relaxant activities on vascular smooth muscles in vitro and in vivo. In particular, PGI2 and TXA2 , produced abundantly by vascular endothelial cells and platelets, respectively, are a potent vasodilator and vasoconstrictor, respectively. It is therefore interesting to study how these PGs contribute to the regulation of the cardiovascular system. Murata et al. [23] created mice deficient in the IP receptor and found that while IP-deficient mice lack the hypotensive response to the synthetic IP agonist cicaprost, their basal blood pressure and heart rate were not different from those of control animals. This result indicates that the PGI2 and IP system does not work constitutively in regulating the systemic circulation but more likely works on demand in response to local stimuli. PGI2 and TXA2 also act on platelets to inhibit or induce, respectively, platelet activation and aggregation. Because of their opposite actions on blood vessels and platelets, it has been proposed that a balance between the PGI2 and TXA2 systems is important for maintaining vascular homeostasis (i.e. to prevent thrombosis and vasospasm while performing efficient hemostasis). A study on IP-deficient mice showed that they develop and age normally. No increased occurrence of vascular incidents was observed. This suggests that in the absence of other predisposing factors, mice can survive safely without the action of PGI2 . However, an enhanced thrombotic tendency was observed in IP-deficient mice when endothelial damage was evoked. These findings confirmed the long proposed role of PGI2 as an endogenous antithrombotic agent and suggest that this antithrombotic system is activated in response to vascular injury to attenuate its effects. In contrast to PGI2 , TXA2 has been implicated in thrombosis and hemostasis on the basis of its proaggregatory and vasocontractile activities. Indeed, TP-deficient mice showed increased bleeding tendencies and were resistant to cardiovascular shock induced by intravenous infusion of a TP agonist, U-46619, and arachidonic acid [46]. The increased bleeding tendency has also been noted in patients with a TP receptor abnormality caused by an Arg to Leu mutation in the receptor. This mutant receptor impairs coupling of the receptor to Gq [47]. Platelets from patients homozygous in this mutation showed no aggregation in response to TXA2 These results suggest that the TXA2 and TP system dose indeed play a physiological role in hemostasis. PGE2 also elicits contractile and/or relaxant responses when tested on vascular smooth muscles in vitro. Kennedy et al. [48] administered PGE2 and PGE analogs intravenously into wild-type and EP2-deficient mice and examined the response in vivo. They observed that

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infusion of PGE2 or an EP2 agonist, butaprost, induces a transient hypotension in wild-type mice, whereas injection of the mixed EP1/3 agonist, sulprostone, resulted in an increase in mean arterial pressure. The hypotensive response to butaprost was not observed, and the hypertensive effects of sulprostone persisted in EP2-deficient mice, and, surprisingly, PGE2 evoked considerable hypertension. The authors suggested that the absence of the EP2 receptor abolishes the ability of the mouse vasculature to vasodilate in response to PGE2 and unmasks the contractile response mediated via the vasoconstrictor EP receptor(s). Interestingly, when fed a high-salt diet, the EP2-deficient mice develop significant hypertension with a concomitant increase in urinary excretion of PGE2 . These results indicate that PGE2 is produced in the body in response to a high-salt diet and works to decrease blood pressure via the relaxant EP2 receptor and that dysfunction of this pathway may be involved in the development of salt-sensitive hypertension. Recently, Audoly et al. [49] compared the roles of individual EP receptors in males and females. They found that the relative contribution of each EP receptor subtype was strikingly different between males and females. In females, the EP2 and EP4 receptors mediate the major portion of the vasodepressor response to PGE2 . In males, the EP2 receptor has a modest role, and most of the vasodepressor effect is mediated by the phospholipase C-coupled EP1 receptor. In addition, in male mice the EP3 receptor actively opposes the vasodepressor actions of PGE2 . Thus, the hemodynamic actions of PGE2 are mediated through complex interactions involving several EP receptor subtypes, and the role of individual EP receptors in males differs dramatically from that in females. 5.2. Vascular remodeling: closure of ductus arteriosus At birth, mammals including humans undergo a dramatic change in their circulation with the commencement of respiration, i.e. from the fetal circulation system that shunts blood flow from the main pulmonary artery directly to the aorta via the ductus arteriosus, to the pulmonary circulation system of the neonate. This adaptive change is caused by the closure of the ductus. The patency of the ductus during the fetal period is believed to be maintained principally by the dilator effects of a prostaglandin, and its closure is induced by withdrawal of the dilator prostaglandins as well as active contraction exerted by an increased oxygen tension [50]. This concept is supported by the fact that administration of aspirin-like drugs or a vasodilator PG such as PGE1 suppresses or maintains, respectively, the patency of the ductus in neonates with patent ductus arteiosus [50,51]. A study using various synthetic PG analogs suggested that both IP and EP4 receptors are present in the ductus and are involved in the dilation of this vessel [52]. The presence of the EP4 receptor was confirmed by in situ hybridization of its mRNA in the mouse [53,54]. Disruption of the mouse IP gene did not appear to cause any abnormality of the ductus [23]. On the other hand, most EP4-deficient die within 3 days after birth, due to marked pulmonary congestion and heart failure [53,54]. Administration of indomethacin into maternal mice during late pregnancy elicited premature closure of the ductus in wild-type fetuses, but not in the ductus of EP4-deficient fetuses, indicating that the dilatory effect of PGE2 on this vessel is mediated by the EP4 receptor [53]. These results suggest a critical role for the EP4 receptor in the ductus and can be interpreted to mean that in the absence of the EP4 receptor a compensatory mechanism maintains ductus patency not only in the fetal period but also after birth.

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6. Receptors mediating reproduction 6.1. Ovulation and fertilization Recent studies on COX-2-deficient mice (but not COX-1-deficient mice) showed multiple reproductive failures in early pregnancy, such as in ovulation, fertilization, implantation, and decidualization, suggesting that PGs play essential roles in these processes [55,56]. Because IP-, EP1-, EP3-, EP4-, and TP-deficient females are fertile, these receptors may be dispensable in female reproduction. Recently, three groups reported reproductive failure in early pregnancy in EP2-deficient female mice [48,57,58]. Kennedy et al. [48] and Tilley et al. [58] found that EP2-deficient female mice consistently deliver fewer pups than their wild-type counterparts irrespective of the genotypes of mating males. They detected slightly impaired ovulation and a dramatic reduction in fertilization in EP2-deficient mice and concluded that the reproductive failure during early pregnancy in COX-2-deficient mice is due to dysfunction of the EP2 receptor. Hizaki et al. [57] further found that this phenotype is due to impaired expansion of the cumulus of oophorus. Because the EP2 receptor and COX-2 are induced in the cumulus in response to gonadotropins and PGE2 can induce cumulus expansion by elevating cAMP, these authors proposed that the PGE2 and EP2 receptor system works as a positive-feedback loop to induce the oophorus maturation required for fertilization during and after ovulation. Indeed unovulated eggs remaining in the corpora lutea were observed at a higher rate in EP2-deficient mice. It is interesting in this respect that indomethacin treatment results in the formation of luteinized unruptured follicles in humans [59]. As described above, it has been suggested that COX-2 and its products contribute to implantation. The EP2 receptor may play a role in this process since its mRNA is highly induced in luminal epithelial cells during the preimplantation period via a steroid-dependent pathway [60,61]. However, the uteri of EP2-deficient females appear normal in their ability to support implantation of wild-type embryos. One possibility is that EP4 expression in the luminal epithelium can compensate for the EP2 receptor in implantation. Recently, Lim et al. [62] reported that the impaired ability for implantation in COX-2-deficient mice is reversed by both PGI2 analogs and an agonist for PPAR␦. They proposed that COX-2-derived PGI2 may participate in implantation through PPAR␦. This interesting finding should be carefully interpreted and verified using PPAR␦-deficient mice or PPAR␦ antagonists, particularly because the doses of PGI analogs used in this study were higher than physiological conditions. 6.2. Leuteolysis and parturition PGF2␣ is accepted as an inducer of leuteolysis in domestic animals such as the sheep and cow, and has been implicated in parturition via its action as a strong uterotonic substance. However, the FP-deficient mice did not show any abnormalities in early pregnancy, and there were no changes in the estrous cycle. The latter finding appears enigmatic at first glance, since the FP receptor is abundantly expressed in the corpora lutea in the ovary of mice with normal estrous cycles [63], and the expression of FP mRNA is closely associated with luteal cell apoptosis in pseudopregnancy [64]. However, this may be due to the fact

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that luteolysis is not required for entrance into a new estrous cycle in mice and that their ovaries contain corpora lutea from a few previous estrous cycles. Thus, PGF2␣ synthesis and action may not always be synchronized with the estrous cycle in mice, although the FP receptor is still present in the corpora lutea in these animals [65,66]. Sugimoto et al. [67] found that, despite no alteration in the above processes, FP-deficient mothers do not undergo parturition, apparently due to the lack of labor. They further found that FP-deficient mice do not undergo parturition even when given exogenous oxytocin and that they show no prepartum decline in progesterone. A reduction in progesterone levels by ovariectomy 24 h before term resulted in an upregulation of uterine receptors for oxytocin and normal parturition in FP-deficient mice. These experiments indicate that the luteolytic action of PGF2␣ is required in mice to diminish progesterone levels and thus permit the initiation of labor. These experiments also indicate that the uterotonic action of PGF2␣ in myometrium is not essential for parturition. It has been shown in many species that a large amount of PGs is produced in intrauterine tissues during labor, but the exact roles of these PGs remain unknown. The luteolytic role of PGF2␣ in the induction of labor is also supported by the finding that mice lacking the gene encoding COX-1 exhibited a similar failure of parturition [68]. In these mice, production of PGF2␣ in intrauterine tissues during late pregnancy is significantly reduced and the administration of PGF2␣ on day 19 is able to restore normal parturition. In wild-type mice, uterine expression of COX-1 mRNA gradually increases from day 15 of pregnancy, reaches maximal levels on day 17, and rapidly decreases after day 20, the day when parturition normally occurs. Tsuboi et al. [69] found that the uterine expression of COX-1 mRNA was still at high levels on day 20 in FP-deficient mice. This observation suggests that progesterone withdrawal could serve as a negative feedback system for uterine COX-1 expression.

7. Receptors mediating gastrointestinal functions The PGs are widely distributed in the digestive system and are involved in a number of physiological processes including motility, blood flow, water and electrolyte absorption, and mucus secretion. In addition, treatment with aspirin-like drugs are known to reduce the risk of colorectal neoplasia, and the involvement of PGE2 in the proliferative activity of the colonic epithelium has been suggested. In spite of the accumulating evidence for the involvement of PGs in these physiological and pathophysiological processes, little is known about the receptor types involved in each of the processes occurring in the gastrointestinal tract. Studies with EP and other prostanoid receptor-deficient mice have been useful for clarifying this issue. Takeuchi et al. [70] found that EP3 but not EP1 is involved in acid-induced duodenal bicarbonate secretion, which is physiologically important in mucosal defense against acid injury. Recently, Boku et al. [71] reported that endogenous PGI2 , but not PGE2 had a role in adaptive cytoprotection of gastric mucosa. Preperfusion with mildly hypertonic saline (1 M NaCl) increases generation of gastric PGE2 and PGI2 and reduces the extent of the subsequent ethanol-induced mucosal damage. Application of 1 M NaCl to IP receptor-deficient mice did not elicit the protective effects seen in the wild-type mice toward ethanol-induced gastric mucosal lesions.

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The rationale for COX isoforms and their products having roles in the development of colon cancer are based on both human epidemiological data and experiments with rodents. Epidemiological studies have indicated that aspirin reduces colon cancer mortality in humans [72,73]. Rao et al. [74] have conducted many studies indicating that aspirin-like drugs reduce carcinogen-induced intestinal cancer in rodents. Further support for a role of COX-2 in intestinal neoplasia has been presented by Oshima et al. [75], who showed that genetic disruption of COX-2 reduces the number and size of the intestinal polyps dramatically in Apc-knockout mice. Inhibition of polyp formation in the Apc-knockout mice was also observed upon treatment with a COX-2-selective inhibitor. These results suggested that COX-2 contributes to an early event of the tumorigenesis. However, it has not been determined which type of prostanoid or prostanoid receptor mediates this action. Sonoshita et al. [76] reported that homozygous disruption of the EP2 receptor in Apc-knockout mice caused significant decreases in the number and size of the intestinal polyps, effects similar to those induced by COX-2 gene disruption. As for the mechanism, they proposed that increased cellular cAMP levels involving the PGE2 –EP2 receptor signaling amplify COX-2 and stimulate the expression of vascular endothelial growth factor (VEGF) in the polyp stroma. On the other hand, Watanabe et al. [77] explored this issue by using EP1- and EP3-knockout mice in a different model of colon carcinogenesis. Treatment of EP3-deficient mice with the colon carcinogen, azoxymethane causes aberrant crypt foci, putative preneoplastic lesions of the colon with an incidence similar to that of wild-type mice. In contrast, foci formation was decreased in EP1-deficient mice to ∼60% of the level of wild-type mice. Furthermore, partial reduction of foci formation was observed following the administration of an EP1-specific antagonist, ONO-8711 in the diet of azoxymethane-treated C57BL/6J mice. A similar treatment also reduced the number of polyps in Min mice. These results suggest that PGE2 contributes to colon carcinogenesis to some extent through its action on the EP1 receptor. Thus, there remain discrepancies regarding the identity of the EP receptor acting in carcinogenesis. It is noted with this receptor that the preventative potencies of EP1 deficiency or EP1 antagonists on colon carcinogenesis are less than those observed with COX-2-selective inhibitors, suggesting the involvement of additional prostanoid receptors other than the EP1 receptor in this process.

8. Receptors mediating bone metabolism Bones undergo continuous destruction and renewal, a process termed bone remodeling. Bone resorption is carried out by osteoclasts, and bone formation, by osteoblasts. These events are controlled by systemic humoral factors such as parathyroid hormone, estradiol, and Vitamin D as well as by local cytokines such as IL-1␤, IL-6, and insulin-like growth factor. Prostaglandins, particularly of the E type, can also affect bone remodeling, in both bone formation and resorption. The bone resorptive activity of PGE is associated with an increase in the number of osteoclasts. Sakuma et al. [78] and Miyaura et al. [79] reported impaired osteoclast formation in cells cultured from EP4-deficient mice. Sakuma et al. used several PGE analogs in cocultures of primary osteoblasts and bone marrow cells that contain osteoclast precursors and found that osteoclast formation is most potently induced by analogs with EP4 receptor agonist activity. Based on this finding, they suggested that the EP4

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receptor is the PGE receptor subtype involved in osteoclast induction. Indeed, PGE2 -induced osteoclast formation was impaired in cultures of osteoblasts from EP4-deficient mice and osteoclast precursors from the spleen of wild-type mice. Interestingly, IL-1␣, TNF-␣, and basic fibroblast growth factor fail to induce osteoclast formation in these cultures. Miyaura et al. [79] added PGE2 to cultures of parietal bone from mice deficient in each of the PGE receptor subtype as well as wild-type mice and examined the bone resorptive activity of this PG by measuring Ca2+ released into the medium. They found that bone resorption by PGE2 was much decreased in bones from EP4-deficient mice, which, on the other hand, showed an equal extent of response to dibutyryl cAMP added to the culture as the bones from control mice. These studies unequivocally establish the role of the EP4 subtype of PGE receptors in PGE2 -mediated bone resorption. On the other hand, Li et al. [80] reported that the osteoclastogenic response to PGE2 , parathyroid hormone, and 1,25-dihydoxyvitamin D in vitro is reduced significantly in cultures of cells from EP2-deficient mice. This apparent discrepancy is likely to reflect redundant roles of the two relaxant PGE receptor subtypes. Sakuma and Miyaura found a small but significant PGE2 -dependent response in EP4-deficient mice, and Li reported a further decrease in osteoclastogenesis when an EP4-selective antagonist was added to EP2-deficient cells. Redundant roles for prostanoid receptors of the relaxant class are also seen in macrophages, where EP2, EP4, and IP regulate production of cytokines in a similar fashion [45]. The contribution of the EP4-mediated process to bone resorption under various physiological and pathophysiological conditions in intact mice has not been fully examined, because an adequate number of EP4-deficient mice are not available (because of their premature death from patent ductus arteriosus). In addition to bone resorption, PGE2 added exogenously also induces bone formation. Recently, Yoshida et al. infused PGE2 into the periosteal region of the femur of wild-type or mice deficient in each EP subtype using a mini-osmotic pump [81]. After 6 weeks, the femur was isolated and bone formation was examined. Radiographic analysis revealed that PGE2 induced extensive callus formation on the femur at the site of infusion in wild-type, EP1-, EP2- and EP3-deficient mice. In contrast, no bone formation was detected radiographically in EP4-deficient mice. Consistently, bone formation was induced in wild-type mice by infusion of an EP4-selective agonist, but not by agonists specific for other EP subtypes. Yoshida et al. next used rats subjected to ovariectomy or immobilization, and examined the effects of the EP4-selective agonist treatment on the bone loss induced by either condition. The addition of the EP4-selective agonist potently prevented the bone loss in both cases and restored the bone mass. Consistently, the histomorphometric analysis revealed that the density of osteoblasts lining the bone surface increased with the increase in the bone mass. These results suggest that EP4 is responsible for both bone resorption and bone formation induced by PGE2 and that activation of EP4 induces bone remodeling in vivo.

9. Perspectives As reviewed in this chapter, studies with knockout mice on the prostanoid receptors have identified and are identifying the types and subtypes of receptors mediating various physiological and pathophysiological actions of prostanoid. As seen in the analysis of DP-KO mice in the allergic asthma, these studies have also revealed prostanoid actions that have not been

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predicted by the effects of aspirin-like drugs, and thus, are providing significant information for development of new therapeutics that selectively stimulate or inhibit each PG receptor. Indeed, some of the knockout mouse phenotypes have been confirmed and reproduced by the use of newly developed compounds selective to each type or subtype of receptor. The knockout mice studies may also give us some indication as to the susceptibility of humans to certain diseases. As shown with aspirin-induced asthma and exacerbation of inflammatory bowel diseases by aspirin-like drugs, a critical involvement of prostanoid-formation occurs in certain populations of patients with several different diseases. The findings with knockout mice deficient in each prostanoid receptor certainly will facilitate a search for single nucleotide polymorphisms in the genes of the respective human prostanoid receptors as causative factors in related diseases. Already a polymorphic variation of the human TP gene has been identified, and its potential connection to allergic diseases was described [82]. Finally, it should be noted that the prostanoid receptor family may not be limited to just eight types of the receptors discussed in this article. Hirai et al. [83] recently identified an orphan receptor termed CRTH2 as a new type of receptor for PGD2 . This receptor does not belong to the prostanoid receptor family discussed here but to the chemokine receptor family. Apparently, this receptor has evolved differently, and this raises the possibility that there may be unknown receptors or even unknown families of receptors for prostanoids. Elucidation and analysis of the complete human and mouse genome sequences may clarify these issues. References [1] Kluger MJ. Fever: role of pyrogens and cryogens. Physiol Rev 1991;71:93–127. [2] Saper CB, Breder CD. The neurologic basis of fever. N Engl J Med 1994;330:1880–6. [3] Ushikubi F, Segi E, Sugimoto Y, Murata T, Matsuoka T, Kobayashi T, et al. Impaired febrile response in mice lacking the prostaglandin E receptor subtype EP3. Nature 1998;395:281–4. [4] Stitt JT. Evidence for the involvement of the organum vasculosum laminae terminalis in the febrile response of rabbits and rats. J Physiol (Lond) 1985;368:501–11. [5] Stitt JT. Prostaglandin E as the neural mediator of the febrile response. Yale J Biol Med 1986;59:137–49. [6] Cao C, Matsumura K, Yamagata K, Atanabe Y. Induction by lipopolysaccharide of cyclooxygenase-2 mRNA in rat brain: its possible role in the febrile response. Brain Res 1995;697:187–96. [7] Li S, Wang Y, Matsumura K, Ballou LR, Morham SG, Blatteis CM. The febrile response to lipopolysaccharide is blocked in cyclooxygenase-2 (−/−), but not in cyclooxygenase-1 (−/−) mice. Brain Res 1999;825:86–94. [8] Ek M. Pathway across the blood-brain barrier. Nature 2001;410:430–1. [9] Yamagata K, Matsumura K, Inoue W, Shiraki T, Suzuki K, Yasuda S, et al. Coexpression of microsomal-type prostaglandin E synthase with cyclooxygenase-2 in brain endothelial cells of rats during endotoxin-induced fever. J Neurosci 2001;21:2669–77. [10] Scammell TE, Elmquist JK, Griffin JD, Saper CB. Ventromedial preoptic prostaglandin E2 activates fever-producing autonomic pathways. J Neurosci 1996;16:6246–54. [11] Stitt JT. Differential sensitivity in the sites of fever production by prostaglandin E1 within the hypothalamus of the rat. J Physiol (Lond) 1991;432:99–110. [12] Matsuda T, Hori T, Nakashima T. Thermal and PGE2 sensitivity of the organum vasculosum lamina terminalis region and preoptic area in rat brain slices. J Physiol (Lond) 1992;454:197–212. [13] Matsumura K, Watanabe Y, Onoe H, Watanabe Y, Hayaishi O. High density of prostaglandin E2 binding sites in the anterior wall of the 3rd ventricle: a possible site of its hyperthermic action. Brain Res 1990;533:147–51. [14] Matsumura K, Watanabe Y, Imai-Matsumura K, Connolly M, Koyama YY, Onoe H, et al. Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography. Brain Res 1992;581:292–8.

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