Prostaglandin E2–EP3 signaling suppresses skin inflammation in murine contact hypersensitivity

SummaryProstaglandin E2 (PGE 2 ) is produced in inflammatory responses and regulates a variety of immunological reactions through 4 different receptor subtypes; EP1, 2, 3 and 4. However, the precise role of each receptor in cardiovascular disease has not yet been elucidated. Enhanced expression of some EPs has been observed in clinical and experimental cardiovascular diseases. EP agonists have been developed to clarify the role of each receptor. Recently, we developed a novel selective agonist to examine the effects of EP4 on cardiac transplantation, myocardial ischemia, and myocarditis. Of note, a selective EP4 agonist attenuated inflammatory cytokines and chemokines via attenuation of macrophage activation in inflammatory heart diseases. In this review article, we discuss the effects of PGE 2 receptor agonists on the development of cardiovascular diseases. (Int Heart J 2011; 52: 266-269) Key words: Prostaglandin, Receptors, Chemokine, Macrophage, Heart P rostanoids are known to be multifunctional physiologic factors. They are produced by various stimuli and participate in local homeostasis and physiologic responses. They are synthesized from arachidonic acid and quickly released to the extracellular medium to send signals via prostanoid receptors.1) The prostanoid receptors, DP, EP, FP, IP and TP, are bound to PGD 2 , PGE 2 , PGF 2α , PGI 2 , and TXA 2 , respectively. 2)In the cardiovascular system, these receptors are expressed on various cells, such as cardiomyocytes, vascular endothelium and smooth muscle cells.3) They play an important role in modulating homeostasis in the development of cardiovascular diseases, such as thrombosis and atherosclerosis.4) Recent studies revealed that prostanoids play an important role in both the occurrence and suppression of various cardiovascular diseases, such as myocardial ischemia, cardiac hypertrophy, cardiac fibrosis, and atherosclerosis. 5) However, the detailed roles of prostanoids in cardiovascular disease have not yet been completely elucidated. To clarify the mechanisms, selective receptor agonists have been developed.Among the prostanoids, PGE 2 is known to play a key role in the pathogenesis of cardiovascular diseases. It was reported that a deficiency of PGE 2 synthase-1 reduced plaque burden in fat-diet low-density lipoprotein receptor knockout mice.6) Another report revealed that PGE 2 synthase-1 knockout mice showed impaired left ventricular contraction after acute myocardial infarction.7) These studies indicate that PGE 2 plays a pivotal role in cardiovascular inflammation. 8, 9) PGE 2 exerts their effects via G-protein-coupled receptors, and PGE 2 -mediated cardioprotection is involved in the EP receptor subtypes. 10)Each receptor has their unique signaling pathways. EP1 couples to Gq and increases intracellular Ca . EP3 couples to Gi and inhibits the increase of cAMP. EP2 and EP4 receptors are coupled to stimulate adenylate cyclase, which leads to the elevation of intracellular cAMP.11) In these EP receptors, EP3 and EP4 are known to have cardioprote...

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“…28) Sulprostone is known to stimulate duodenal HCO 3 (-) secretion and the response was inhibited by AE5-599 (EP3 antagonist).…”

Section: Synthesized Ep Agonists I) Ep1 Agonistsmentioning

confidence: 99%

Roles of Prostaglandin E2 in Cardiovascular Diseases

et al. 2011

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“…As in most cutaneous inflammatory conditions, atopic dermatitis is characterised by increased PLA 2 activity [114] with COX-derived prostanoids apparently more involved than LOX-derived mediators [115]; a similar profile also observed in contact dermatitis [26].…”

Section: Atopic Dermatitismentioning

confidence: 71%

“…It exhibits potent pro-inflammatory and vasodilatory properties, promotes proliferation and modulates immunosuppression [22,23]. These effects are mediated through G-protein coupled receptors EP1-4 expressed in all primary skin cells [24][25][26][27]. PGE 2 is formed via the cytosolic and microsomal PGE synthases (cPGES, mPGES-1 and mPGES-2) [28].…”

Section: Cyclooxygenase-derived Mediatorsmentioning

confidence: 99%

“…PGD 2 is one of the principle prostanoids involved in atopic dermatitis because of its immunomodulatory properties and the active role of Langerhans cells and mast cells (the main cutaneous courses of PGD 2 ) in this primarily immunological problem [21,117]. Finally, the vasoactive PGI 2 and immunosuppressive PGE 2 have also been suggested to be actively involved [26,53]. In vitro studies with GLA and DHA suggest that PUFA can alter the profile of eicosanoids produced by cutaneous immune cells and, in this way, improve atopic dermatitis [118].…”

Section: Atopic Dermatitismentioning

confidence: 99%

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Eicosanoids in skin inflammation

Nicolaou

2013

Prostaglandins, Leukotrienes and Essential Fatty Acids

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SummaryEicosanoids play an integral part in homeostatic mechanisms related to skin health and structural integrity. They also mediate inflammatory events developed in response to environmental factors, such as exposure to ultraviolet radiation, and inflammatory and allergic disorders, including psoriasis and atopic dermatitis. This review article discusses biochemical aspects related to cutaneous eicosanoid metabolism, the contribution of these potent autacoids to skin inflammation and related conditions, and considers the importance of nutritional supplementation with bioactives such as omega-3 and omega-6 polyunsaturated fatty acids and plant-derived antioxidants as means of addressing skin health issues.2

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“…Collectively, blockage of PGD 2 -CRTH2 signaling might inhibit allergic skin inflammation elicited in patients with AD by re-exposure to antigens to which they have been sensitized (Figure 3). In contrast, stimulation of EP3-signaling in KCs is reported to play an anti-inflammatory role in skin inflammation by inhibiting chemokine production from KCs (Honda et al, 2009). Administration of an EP3 specific agonist suppressed a CHS response, and EP3 knockout mice showed an enhanced CHS response, suggesting that PGE 2 -EP3 signaling works as a negative regulator of allergic cutaneous inflammation.…”

Section: Prostanoids As Inflammatory Mediatorsmentioning

confidence: 98%