PGE2 functie-spectrum – The PGE2 Hypothesis: An integrative hypothesis for Long COVID and related syndromes

The wideranging functions of prostaglandin E2 and its EP receptors

Table 1. Long COVID associated SYMPTOMS AND COMORBIDITIES STIMULATED BY PGE2

Apnea⁽¹⁾ Anemia⁽²⁾ Atherosclerosis⁽³⁾ Asthma⁽⁴⁾ Alzheimer⁽⁵⁾ Autonomic Dysfunction⁽⁶⁾ Bronchoconstriction⁽⁷⁾ Cancer⁽⁸⁾ Cough⁽⁹⁾ Cardiac Hpertrophy⁽¹⁰⁾ Cardiomyopathy⁽¹¹⁾ Type 1 Diabetes ⁽¹²⁾ Type 2 Diabetes ⁽¹³⁾ Dysmenorrhoea⁽¹⁴⁾ Depression⁽¹⁵⁾ Endothelial Dysfunction⁽¹⁶⁾ Gastro-intestinal inflammation ⁽¹⁷⁾ IBS⁽¹⁸⁾ Low Blood Pressure⁽¹⁹⁾ Lymphopenia⁽²⁰⁾ Malaise/Aversion⁽²¹⁾ Migraine⁽²²⁾ Mitochondrial Dysfunction^(23-25) Muscle weakness⁽²⁶⁾ Myalgia⁽²⁷⁾ Obesity⁽²⁸⁾ Nausea⁽²⁹⁾ Neurological conditions⁽³⁰⁾ Osteoarthritis⁽³¹⁾ Pain⁽³²⁾ Parkinson⁽³³⁾ (Acute) Kidney Injury^{(34, 35)} Respiratory problems (Asthma)^{(36) (37)} Sleep/Wake problems via EP2/COX2/PGD2⁽³⁸⁾ Thirst⁽³⁹⁾ Thrombotic problems via EP3⁽⁴⁰⁾ and via EP2>COX2>TXA2⁽⁴⁹⁾

Table 2. RECEPTORS EP1 -EP4, AN OVERVIEW (not exhaustive)
EP4^(41-43)	EP3^(41-43)	EP2^(41-43)	EP1^(41-43)
EP4 has the most affinity for PGE2 of these four receptors ⁽⁴¹⁾	EP3 has less affinity for PGE2 than EP4⁽⁴¹⁾	EP2 has less affinity for PGE2 than EP4⁽⁴¹⁾	PGE2 binds the weakest to EP1⁽⁴¹⁾
G-proteïn-coupled⁽⁴¹⁾	G-proteïn-coupled or CA2+ stimulated⁽⁴¹⁾	G-proteïn-coupled⁽⁴¹⁾	CA2+ stimulated⁽⁴¹⁾
cAMP upregulation⁽⁴¹⁾	cAMP downregulation⁽⁴¹⁾	cAMP upregulation⁽⁴¹⁾
EP4 desensitizes quickly (when stimulated by a sufficient high level of PGE2 it rapidly internalizes: it moves to the inside of the cell membrane)⁽⁴¹⁾	Eight splice variants of this receptor have been identified, some of these upregulate cAMP^{(44, 45)}	EP2-function is often similar to EP4- function, but PGE2-action through EP2 lasts longer⁽⁴¹⁾	Two splice variants have been identified. EP1- function is often similar to EP3- function⁽⁴¹⁾


Relaxation of smooth muscle⁽⁴⁶⁾	Contraction of smooth muscle⁽⁴⁶⁾	Relaxation of smooth muscle⁽⁴⁶⁾	Contraction of smooth muscle⁽⁴⁶⁾
Vasodilatation ⁽⁴⁶⁾	Vasoconstriction ⁽⁴⁶⁾	Vasodilatation⁽⁴⁶⁾	Vasoconstriction⁽⁴⁶⁾
Decreasing BP⁽⁴⁶⁾	Increasing BP⁽⁴⁶⁾	Decreasing BP⁽⁴⁶⁾	Increasing BP⁽⁴⁶⁾
Antidiuretic⁽⁴⁶⁾	Diuretic⁽⁴⁶⁾ Antidiuretic under high salt conditions	Antidiuretic⁽⁴⁶⁾	Diuretic⁽⁴⁶⁾
PGE2 the major lipid mediator of inflammation stimulates:
through EP4	through EP3	through EP2	through EP1
anti-inflammatory processes, ao downregulating CD4+ activity, stimulating anti-inflammatory cytokines such as il-10⁽⁴⁷⁾	inflammatory processes, ao upregulating inflammatory cytokines such as il-6⁽⁴⁸⁾	by stimulating COX > upregulation of its own production and that of other prostaglandins of the 2-series like PGD2, PGI2 and TXA2⁽⁴⁹⁾	an unknown ligand through EP1 can attenuate PGE2 activity through degradation of COX-2^{(52, 53)}
induces chronic inflammation and various autoimmune diseases through EP4 and EP2 receptors^{(43, 50)}	induces acute and chronic inflammation, through mast cell activation and T helper differentiation respectively⁽⁵⁰⁾ (down)regulates expression of COX-2 in the kidney⁽⁵¹⁾	induces chronic inflammation and various autoimmune diseases through EP4 and EP2 receptors^{(43, 50)}
EP-receptors are expressed on the membranes of all cells, also in the brain, on the membranes of mitochondria⁽⁵⁴⁾ and on the nuclear envelope⁽⁵⁵⁾
Expression of EP4 In the brain and the CNS and on the membrane of mitochondria, of the nucleus and of cells in the majority of tissues⁽⁴¹⁾	Expression of EP3 In the brain and the CNS and on the membrane of mitochondria, of the nucleus and of cells in the majority of tissues⁽⁴¹⁾	Expression of EP2 In the brain and the CNS. EP2 expression is also detected in lung, kidney, intestinal, glandular tissues, bone marrow, spleen, thymus, tonsils, mucous membranes, and skin⁽⁴¹⁾	Expression of EP1 The EP1 receptor mRNA is ubiquitously expressed and EP1 receptor functions as a constrictor in the smooth muscles of the trachea, gastrointestinal tract, bladder, uterus and is especially expressed in the nervous system⁽⁴¹⁾

PGE2 through EP4	PGE2 through EP3	PGE2 through EP2	PGE2 through EP1
Metabolic ▪ Protects against apoptosis of insulin- producing bèta-cells⁽⁶¹⁾ ▪ Regulates bile acid synthesis, protecting against hyper- cholesterolemia⁽⁶²⁾	Metabolic ▪ Apoptosis of insulin- producing bèta-cells⁽¹²⁾ ▪ Negatively regulates glucose-stimulated insulin secretion (GSIS)⁽⁵⁶⁾ ▪ Attenuates lipolysis^(57-59) ▪ Attenuates glycogenolysis ⁽⁶⁰⁾
Apoptotic ▪ Apoptosis of insulin producing bèta-cells⁽¹²⁾ ▪ Apoptosis of neutrophils⁽⁶³⁾	Apoptotic ▪ Protects against apoptosis of insulin producing bèta-cells⁽⁶¹⁾	Apoptotic ▪ Stimulates apoptosis of oligodendrocyte precursor cells (OPC)⁽⁶⁴⁾that produce myelin ▪ Apoptosis of neuronal cells in skeletal-muscle⁽⁶⁵⁾	Apoptotic ▪ Apoptosis of dopaminergic cells in the substantia nigra^{(66, 67)}
Brain processes ▪ Inhibition of noradrenergic neurons in the LC⁽⁶⁸⁾	Brain processes ▪ Vasodilation involved in migraine⁽²²⁾ ▪ Anxiolytic-like activity⁽⁶⁹⁾	Brain processes ▪ Demyelination of nerves, neurotoxicity / cognitive decline by impairing myeloid metabolism^(70-73) ▪ Regulates neurotoxicity induced by aggregated alpha-synuclein⁽⁷²⁾	Brain processes ▪ GABA -mediated inhibition of dopaminergic neurons in the midbrain⁽⁶⁹⁾ ▪ inflammation-induced aversion^(74,75) ▪ Anxiolytic-like activity⁽⁶⁹⁾ ▪ Suppressing impulse behaviour⁽⁷⁶⁾
Nervous system ▪ Inflammatory pain⁽⁷⁹⁾	Nervous system ▪ Inhibiting endogenous pain control ⁽⁷⁷⁾ ▪ Modulating signaling in the autonomic nervous system (PSN and SNS) ^{(6, 78)}	Nervous system ▪ Stimulates apoptosis of oligodendrocyte precursor cells (OPC)⁽⁶⁴⁾that produce myelin ▪ Apoptosis of neuronal cells in skeletal-muscle⁽⁶⁵⁾	Brain processes (follow-up) ▪ EP1 receptor activation increases the probability of status epilepticus and independently promotes hippocampal neurodegeneration⁽⁸⁰⁾ ▪ Behavioral alterations (social avoidance) caused by repeated stress^{(81, 82)} Nervous system ▪ Pain perception⁽⁴⁷⁾
Gastro-intestinal ▪ Inhibition of stomach acid secretion⁽⁸³⁾ ▪ Bicarbonate secretion in stomach and duodenum⁽⁸³⁾	Gastro-intestinal ▪ Stimulating mucus secretion⁽⁸³⁾ ▪ Bicarbonate secretion in the duodenum⁽⁸³⁾	Gastro-intestinal	Gastro-intestinal ▪ functions as a constrictor in the smooth muscles of the gastrointestinal tract⁽⁴⁶⁾ ▪ Inhibition of gastric motility⁽⁸³⁾ ▪ Bicarbonate secretion in the stomach⁽⁸³⁾ ▪ Cytoprotection in the stomach⁽⁸⁴⁾
Bone, cartilage, muscles ▪ Cell-proliferation for muscle and bone and other tissue repair ▪ osteoarthritis^{(85, 86)}	Bone, cartilage, muscles ▪ functions as a constrictor⁽⁴⁶⁾	Bone, cartilage, muscles ▪ Apoptosis of neuronal cells in skeletal-muscle⁽⁶⁵⁾ ▪ Myalgia^{(27, 87)}	Bone, cartilage, muscles ▪ functions as a constrictor in the smooth muscles of the bladder and uterus⁽⁴⁶⁾, possibly involved in the promotion of labor and dysmennorrhea
Cardiovascular ▪ Endothelial barrier integrity ^(90-92) ▪ Inflammatory reaction in atherosclerotic plaques⁽⁹³⁾	Cardiovascular ▪ Reduced contractility of the heart⁽⁸⁸⁾ ▪ Cardiac hypertrophy⁽⁸⁹⁾ ▪ Coagulation thrombosis⁽⁴⁰⁾	Cardiovascular	Cardiovascular
Lungs ▪ a key role for EP2 and EP4 receptors in microvascular leak (MVL) induced by PGE2⁽³⁶⁾	Lungs ▪ Broncho-constriction, cough^{(7, 94)}	Lungs ▪ Inhibition of bronchoconstriction⁽⁹⁵⁾ Suppresses lung innate immunity⁽⁹⁶⁾ ▪ Suppresses allergic sensitization and lung-inflammation⁽⁹⁷⁾	Lungs ▪ functions as a constrictor in the smooth muscles of the trachea⁽⁴⁶⁾
Kidneys	Kidneys (EP3) EP3 (down)regulates expression of COX-2 in the kidneys⁽⁵¹⁾ Water retention under high salt conditions⁽⁹⁸⁾ Edema^{(43, 99)} Role in AKI⁽³⁴⁾ Attenuates reabsorption/Role in polyuria⁽³⁹⁾		Kidneys (EP1) ▪ Glomerulo- sclerosis⁽¹⁰⁰⁾ ▪ Main role in renal fibrosis⁽¹⁰¹⁾
	Skin (EP3) ▪ EP3 and EP1 stimulate melanocyte dendricity / skin pigmentation⁽¹⁰²⁾
	Antagonizing other hormones (EP3) ▪ Inhibition of serotonin signaling; inflammatory pain⁽¹⁰³⁾ ▪ Inhibition of release of noradrenaline and serotonin and dopamine^(104-106)
All four EP-receptors stimulate cell-proliferation in specific types of cancer⁽¹⁰⁷⁾

References

1. Herlenius E. An inflammatory pathway to apnea and autonomic dysregulation. Respir Physiol Neurobiol. 2011;178(3):449-57. DOI: 10.1016/j.resp.2011.06.026

2. Lang F, Abed M, Lang E, Föller M. Oxidative stress and suicidal erythrocyte death. Antioxid Redox Signal. 2014;21(1):138-53. DOI: 10.1089/ars.2013.5747

3. Wang W, Liang M, Wang L, Bei W, Rong X, Xu J, et al. Role of prostaglandin E2 in macrophage polarization: Insights into atherosclerosis. Biochem Pharmacol. 2023;207:115357. DOI: 10.1016/j.bcp.2022.115357

4. Machado-Carvalho L, Roca-Ferrer J, Picado C. Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity. Respir Res. 2014;15(1):100. DOI: 10.1186/s12931-014-0100-7

5. Duro MV, Ebright B, Yassine HN. Lipids and brain inflammation in APOE4-associated dementia. Curr Opin Lipidol. 2022 Feb 1;33(1):16-24.DOI: 10.1097/MOL.0000000000000801

6. Z. H. Zhang, Y. Yu, S. G. Wei, Y. Nakamura, K. Nakamura and R. B. Felder. EP₃ receptors mediate PGE₂-induced hypothalamic paraventricular nucleus excitation and sympathetic activation. Am J Physiol Heart Circ Physiol 2011 Vol. 301 Issue 4 Pages H1559-69.
DOI: 10.1152/ajpheart.00262.2011
7. Zhou J, Alvarez-Elizondo MB, Botvinick E, George SC. Adenosine A(1) and prostaglandin E receptor 3 receptors mediate global airway contraction after local epithelial injury. Am J Respir Cell Mol Biol. 2013;48(3):299-305. DOI: 10.1165/rcmb.2012-0174OC

8. Sun X, Li Q. Prostaglandin EP2 receptor: Novel therapeutic target for human cancers (Review). Int J Mol Med. 2018;42(3):1203-14. DOI: 10.3892/ijmm.2018.3744

9. Maher SA, Birrell MA, Belvisi MG. Prostaglandin E2 mediates cough via the EP3 receptor: implications for future disease therapy. Am J Respir Crit Care Med. 2009;180(10):923-8. DOI: 10.1164/rccm.200903-0388OC

10. Meyer-Kirchrath J, Martin M, Schooss C, Jacoby C, Flögel U, Marzoll A, et al. Overexpression of prostaglandin EP3 receptors activates calcineurin and promotes hypertrophy in the murine heart. Cardiovasc Res. 2009;81(2):310-8.
DOI: 10.1093/cvr/cvn312

11. Bryson TD, Harding P. Prostaglandin E2 EP receptors in cardiovascular disease: An update. Biochemical Pharmacology. 2022;195:114858. https://doi.org/10.1016/j.bcp.2021.114858

12. Amior L, Srivastava R, Nano R, Bertuzzi F, Melloul D. The role of Cox-2 and prostaglandin E2 receptor EP3 in pancreatic β-cell death. The FASEB Journal. 2019;33(4):4975-86. DOI: 10.1096/fj.201801823R

13. Wang W, Zhong X, Guo J. Role of 2‑series prostaglandins in the pathogenesis of type 2 diabetes mellitus and non‑alcoholic fatty liver disease (Review). Int J Mol Med. 2021;47(6):114. DOI: 10.3892/ijmm.2021.4947

14. Downie J, Poyser NL, Wunderlich M. Levels of prostaglandins in human endometrium during the normal menstrual cycle. J Physiol. 1974;236(2):465-72.
DOI: 10.1113/jphysiol.1974.sp010446

15. Lieb J, Karmali R, Horrobin D. Elevated levels of prostaglandin E2 and thromboxane B2 in depression. Prostaglandins Leukot Med. 1983;10(4):361-7.
DOI: 10.1016/0262-1746(83)90048-3

16. Yin J, Xia W, Li Y, Guo C, Zhang Y, Huang S, et al. COX-2 mediates PM2.5-induced apoptosis and inflammation in vascular endothelial cells. Am J Transl Res. 2017;9(9):3967-76. PMID: 28979673

17. Takafuji V, Cosme R, Lublin D, Lynch K, Roche JK. Prostanoid receptors in intestinal epithelium: selective expression, function, and change with inflammation. Prostaglandins Leukot Essent Fatty Acids. 2000;63(4):223-35. DOI: 10.1054/plef.2000.0144

18. Grabauskas G, Wu X, Gao J, Li J-Y, Turgeon DK, Owyang C. Prostaglandin E<sub>2</sub>, Produced by Mast Cells in Colon Tissues From Patients With Irritable Bowel Syndrome, Contributes to Visceral Hypersensitivity in Mice. Gastroenterology. 2020;158(8):2195-207.e6. DOI: 10.1053/j.gastro.2020.02.022

19. Yang T, Du Y. Distinct roles of central and peripheral prostaglandin E2 and EP subtypes in blood pressure regulation. Am J Hypertens. 2012;25(10):1042-9.
DOI: 10.1038/ajh.2012.67

20. Gupta A, Chander Chiang K. Prostaglandin D(2) as a mediator of lymphopenia and a therapeutic target in COVID-19 disease. Med Hypotheses. 2020;143:110122.
DOI: 10.1016/j.mehy.2020.110122

21. Fritz M, Klawonn AM, Nilsson A, Singh AK, Zajdel J, Wilhelms DB, et al. Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. J Clin Invest. 2016;126(2):695-705. DOI: 10.1172/JCI83844

22. Antonova M. Prostaglandins and prostaglandin receptor antagonism in migraine. Dan Med J. 2013;60(5):B4635. PMCID: PMC3619997

23. Chen J, Deng JC, Zemans RL, Bahmed K, Kosmider B, Zhang M, et al. Age-induced prostaglandin E(2) impairs mitochondrial fitness and increases mortality to influenza infection. Nat Commun. 2022;13(1):6759. https://doi.org/10.1038/s41467-022-34593-y

24. Bryson TD, Zurek M, Moore C, Taube D, Datta I, Levin A, et al. Prostaglandin E2 affects mitochondrial function in adult mouse cardiomyocytes and hearts. Prostaglandins Leukot Essent Fatty Acids. 2024;201:102614. DOI: 10.1016/j.plefa.2024.102614

25. Franco F, Wenes M, Ho P-C. Sparks Fly in PGE2-Modulated Macrophage Polarization. Immunity. 2018;49(6):987-9. DOI: 10.1016/j.immuni.2018.12.002

26. Liu SZ, Jemiolo B, Lavin KM, Lester BE, Trappe SW, Trappe TA. Prostaglandin E2/cyclooxygenase pathway in human skeletal muscle: influence of muscle fiber type and age. J Appl Physiol (1985). 2016;120(5):546-51. DOI: 10.1152/japplphysiol.00396.2015

27. Hedenberg-Magnusson B, Ernberg M, Alstergren P, Kopp S. Pain mediation by prostaglandin E2 and leukotriene B4 in the human masseter muscle. Acta Odontol Scand. 2001;59(6):348-55. DOI: 10.1080/000163501317153185

28. Fain JN, Ballou LR, Bahouth SW. Obesity is induced in mice heterozygous for cyclooxygenase-2. Prostaglandins Other Lipid Mediat. 2001;65(4):199-209.
DOI: 10.1016/s0090-6980(01)00136-8

29. Gadsby R, Barnie-Adshead A, Grammatoppoulos D, Gadsby P. Nausea and vomiting in pregnancy: an association between symptoms and maternal prostaglandin E2. Gynecol Obstet Invest. 2000;50(3):149-52. DOI: 10.1159/000010314

30. Milatovic D, Montine TJ, Aschner M. Prostanoid signaling: dual role for prostaglandin E2 in neurotoxicity. Neurotoxicology. 2011;32(3):312-9. DOI: 10.1016/j.neuro.2011.02.004

31. Yang D, Xu K, Xu X, Xu P. Revisiting prostaglandin E2: A promising therapeutic target for osteoarthritis. Clin Immunol. 2024;260:109904. DOI: 10.1016/j.clim.2024.109904

32. Kawabata A. Prostaglandin E2 and pain--an update. Biol Pharm Bull. 2011;34(8):1170-3. DOI: 10.1248/bpb.34.1170

33. Ikeda-Matsuo Y, Miyata H, Mizoguchi T, Ohama E, Naito Y, Uematsu S, et al. Microsomal prostaglandin E synthase-1 is a critical factor in dopaminergic neurodegeneration in Parkinson's disease. Neurobiology of Disease. 2019;124:81-92.
DOI: 10.1016/j.nbd.2018.11.004

34. Leng J, Zhao W, Guo J, Yu G, Zhu G, Ge J, et al. E-prostanoid 3 receptor deficiency on myeloid cells protects against ischemic acute kidney injury via breaking the auto-amplification loop of necroinflammation. Kidney International. 2023;103(1):100-14.
DOI: 10.1016/j.kint.2022.08.019

35. Jia Z, Zhang Y, Ding G, Heiney KM, Huang S, Zhang A. Role of COX-2/mPGES-1/prostaglandin E2 cascade in kidney injury. Mediators Inflamm. 2015;2015:147894.
DOI: 10.1155/2015/147894

36. Jones VC, Birrell MA, Maher SA, Griffiths M, Grace M, O'Donnell VB, et al. Role of EP2 and EP4 receptors in airway microvascular leak induced by prostaglandin E2. British journal of pharmacology. 2016;173(6):992-1004. DOI: 10.1111/bph.13400

37. Machado-Carvalho L, Roca-Ferrer J, Picado C. Prostaglandin E2 receptors in asthma and in chronic rhinosinusitis/nasal polyps with and without aspirin hypersensitivity. Respiratory Research. 2014;15(1):100. DOI: 10.1186/s12931-014-0100-7

38. Huang ZL, Urade Y, Hayaishi O. Prostaglandins and adenosine in the regulation of sleep and wakefulness. Curr Opin Pharmacol. 2007;7(1):33-8.
DOI: 10.1016/j.coph.2006.09.004

39. Hassouneh R, Nasrallah R, Zimpelmann J, Gutsol A, Eckert D, Ghossein J, et al. PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes. Diabetologia. 2016;59(6):1318-28.
DOI: 10.1007/s00125-016-3916-5

40. Mawhin MA, Tilly P, Fabre JE. The receptor EP3 to PGE2: A rational target to prevent atherothrombosis without inducing bleeding. Prostaglandins Other Lipid Mediat. 2015 Sep;121(Pt A):4-16. DOI: 10.1016/j.prostaglandins.2015.10.001

41. Biringer RG. A Review of Prostanoid Receptors: Expression, Characterization, Regulation, and Mechanism of Action. J Cell Commun Signal. 2021;15(2):155-84.
DOI: 10.1007/s12079-020-00585-0

42. Markovič T, Jakopin Ž, Dolenc MS, Mlinarič-Raščan I. Structural features of subtype-selective EP receptor modulators. Drug Discovery Today. 2017;22(1):57-71.
DOI: 10.1016/j.drudis.2016.08.003

43. Kawahara K, Hohjoh H, Inazumi T, Tsuchiya S, Sugimoto Y. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. Biochim Biophys Acta. 2015;1851(4):414-21. DOI: 10.1016/j.bbalip.2014.07.008

44. Regan JW, Bailey TJ, Donello JE, Pierce KL, Pepperl DJ, Zhang D, et al. Molecular cloning and expression of human EP3 receptors: evidence of three variants with differing carboxyl termini. Br J Pharmacol. 1994;112(2):377-85.
DOI: 10.1111/j.1476-5381.1994.tb13082.x

45. Israel DD, Regan JW. EP(3) prostanoid receptor isoforms utilize distinct mechanisms to regulate ERK 1/2 activation. Biochim Biophys Acta. 2009;1791(4):238-45.
DOI: 10.1016/j.bbalip.2009.01.021

46. Wang L, Wu Y, Jia Z, Yu J, Huang S. Roles of EP Receptors in the Regulation of Fluid Balance and Blood Pressure. Front Endocrinol (Lausanne). 2022;13:875425.
DOI: 10.3389/fendo.2022.875425

47. HyeonJoo Cheon, Young Hee Rho, Seong Jae Choi, Young Ho Lee, Gwan Gyu Song, Jeongwon Sohn, Nam Hee Won, Jong Dae Ji; Prostaglandin E₂ Augments IL-10 Signaling and Function¹. J Immunol 15 July 2006; 177 (2): 1092–1100. https://doi.org/10.4049/jimmunol.177.2.1092

48. Williams JA, Shacter E. Regulation of macrophage cytokine production by prostaglandin E2. Distinct roles of cyclooxygenase-1 and -2. J Biol Chem. 1997 Oct 10;272(41):25693-9. DOI: 10.1074/jbc.272.41.25693

49. Nam J, Kwon B, Yoon Y, Choe J. PGE2 stimulates COX-2 expression via EP2/4 receptors and acts in synergy with IL-1β in human follicular dendritic cell-like cells. European Journal of Inflammation. 2018;16. DOI:10.1177/2058739218796386

50. Tsuge K, Inazumi T, Shimamoto A, Sugimoto Y. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int Immunol. 2019;31(9):597-606. DOI: 10.1093/intimm/dxz021

51. Vio CP, Quiroz-Munoz M, Cuevas CA, Cespedes C, Ferreri NR. Prostaglandin E2 EP3 receptor regulates cyclooxygenase-2 expression in the kidney. Am J Physiol Renal Physiol. 2012;303(3):F449-57. DOI: 10.1152/ajprenal.00634.2011

52. Haddad A, Flint-Ashtamker G, Minzel W, Sood R, Rimon G, Barki-Harrington L. Prostaglandin EP1 Receptor Down-regulates Expression of Cyclooxygenase-2 by Facilitating Its Proteasomal Degradation. Journal of Biological Chemistry. 2012;287(21):17214-23.
DOI: 10.1074/jbc.M111.304220

53. U. R. Mbonye, C. Yuan, C. E. Harris, R. S. Sidhu, I. Song, T. Arakawa, et al. Two Distinct Pathways for Cyclooxygenase-2 Protein Degradation. Journal of Biological Chemistry 2008 Vol. 283 Issue 13 Pages 8611-8623 DOI: 10.1074/jbc.M710137200

54. Fang KM, Shu WH, Chang HC, Wang JJ, Mak OT. Study of prostaglandin receptors in mitochondria on apoptosis of human lung carcinoma cell line A549. Biochem Soc Trans. 2004;32(Pt 6):1078-80. DOI: 10.1042/BST0321078

55. Bhattacharya M, Peri K, Ribeiro-da-Silva A, Almazan G, Shichi H, Hou X, et al. Localization of functional prostaglandin E2 receptors EP3 and EP4 in the nuclear envelope. J Biol Chem. 1999;274(22):15719-24. DOI: 10.1074/jbc.274.22.15719

56. Kimple ME, Keller MP, Rabaglia MR, Pasker RL, Neuman JC, Truchan NA, et al. Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes. 2013;62(6):1904-12.
DOI: 10.2337/db12-0769

57. Strong P, Coleman RA, Humphrey PP. Prostanoid-induced inhibition of lipolysis in rat isolated adipocytes: probable involvement of EP3 receptors. Prostaglandins. 1992 Jun;43(6):559-66. DOI: 10.1016/0090-6980(92)90115-a

58. Ceddia RP, Lee D, Maulis MF, Carboneau BA, Threadgill DW, Poffenberger G, et al. The PGE2 EP3 Receptor Regulates Diet-Induced Adiposity in Male Mice. Endocrinology. 2016;157(1):220-32. DOI: 10.1210/en.2015-1693

59. Xu H, Fu JL, Miao YF, Wang CJ, Han QF, Li S, et al. Prostaglandin E2 receptor EP3 regulates both adipogenesis and lipolysis in mouse white adipose tissue. J Mol Cell Biol. 2016;8(6):518-29. DOI: 10.1093/jmcb/mjw035

60. Püschel GP, Kirchner C, Schröder A, Jungermann K. Glycogenolytic and antiglycogenolytic prostaglandin E2 actions in rat hepatocytes are mediated via different signalling pathways. Eur J Biochem. 1993;218(3):1083-9.
DOI: 10.1111/j.1432-1033.1993.tb18468.x

61. Carboneau BA, Allan JA, Townsend SE, Kimple ME, Breyer RM, Gannon M. Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation. Molecular Metabolism. 2017;6(6):548-59. DOI: 10.1016/j.molmet.2017.04.002

62. Ying F, Cai Y, Wong HK, Chen XY, Huang IB, Vanhoutte PM, et al. EP4 emerges as a novel regulator of bile acid synthesis and its activation protects against hypercholesterolemia. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2018;1863(9):1029-40. DOI: 10.1016/j.bbalip.2018.06.003

63. Liu J, He H, Zhang Z, Jiang S, Akahoshi T, Yang J, et al. Mitochondria play a role in the development of non-apoptotic programmed cell death of neutrophils induced by ONO-AE-248. Cell Mol Immunol. 2007;4(6):447-53. PMID: 18163956

64. Palumbo S, Toscano CD, Parente L, Weigert R, Bosetti F. The cyclooxygenase-2 pathway via the PGE₂ EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination. J Neurochem. 2012;121(3):418-27.
DOI: 10.1111/j.1471-4159.2011.07363.x

65. Kosuge Y, Nango H, Kasai H, Yanagi T, Mawatari T, Nishiyama K, et al. Generation of Cellular Reactive Oxygen Species by Activation of the EP2 Receptor Contributes to Prostaglandin E2-Induced Cytotoxicity in Motor Neuron-Like NSC-34 Cells. Oxid Med Cell Longev. 2020;2020:6101838. DOI: 10.1155/2020/6101838

66. Carrasco E, Casper D, Werner P. PGE(2) receptor EP1 renders dopaminergic neurons selectively vulnerable to low-level oxidative stress and direct PGE(2) neurotoxicity. J Neurosci Res. 2007;85(14):3109-17. DOI: 10.1002/jnr.21425

67. Ahmad AS, Maruyama T, Narumiya S, Doré S. PGE2 EP1 receptor deletion attenuates 6-OHDA-induced Parkinsonism in mice: old switch, new target. Neurotox Res. 2013;23(3):260-6. DOI: 10.1007/s12640-013-9381-8

68. Mukai Y, Okubo TS, Lazarus M, Ono D, Tanaka KF, Yamanaka A. Prostaglandin E(2) Induces Long-Lasting Inhibition of Noradrenergic Neurons in the Locus Coeruleus and Moderates the Behavioral Response to Stressors. J Neurosci. 2023;43(47):7982-99.
DOI: 10.1523/JNEUROSCI.0353-23.2023

69. Suzuki C, Miyamoto C, Furuyashiki T, Narumiya S, Ohinata K. Central PGE2 exhibits anxiolytic-like activity via EP1 and EP4 receptors in a manner dependent on serotonin 5-HT1A, dopamine D1 and GABAA receptors. FEBS Lett. 2011;585(14):2357-62.
DOI: 10.1016/j.febslet.2011.06.004

70. Lushington R, Camilli S, Pascual F, Lockey RF, Kolliputi N. EP2 inhibition restores myeloid metabolism and reverses cognitive decline. Journal of Allergy and Clinical Immunology: Global. 2023;2(2):100082. DOI: 10.1016/j.jacig.2023.100082

71. Kang X, Qiu J, Li Q, Bell KA, Du Y, Jung DW, et al. Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype. Scientific Reports. 2017;7(1):9459. DOI: 10.1038/s41598-017-09528-z

72. Jin J, Shie FS, Liu J, Wang Y, Davis J, Schantz AM, et al. Prostaglandin E2 receptor subtype 2 (EP2) regulates microglial activation and associated neurotoxicity induced by aggregated alpha-synuclein. J Neuroinflammation. 2007;4:2. DOI: 10.1186/1742-2094-4-2

73. Hu W, Mathey E, Hartung HP, Kieseier BC. Cyclo-oxygenases and prostaglandins in acute inflammatory demyelination of the peripheral nerve. Neurology. 2003;61(12):1774-9.
DOI: 10.1212/01.wnl.0000098884.75756.4d

74. Kitaoka S. Microglia regulate neuronal and behavioural functions under physiological and pathological conditions. J Biochem. 2023 Mar 7;173(3):153-157. PMID: 36539335.
DOI: 10.1093/jb/mvac099

75. Fritz M, Klawonn AM, Nilsson A, Singh AK, Zajdel J, Wilhelms DB, et al. Prostaglandin-dependent modulation of dopaminergic neurotransmission elicits inflammation-induced aversion in mice. J Clin Invest. 2016;126(2):695-705. DOI: 10.1172/JCI83844

76. Furuyashiki T, Narumiya S. Stress responses: the contribution of prostaglandin E(2) and its receptors. Nat Rev Endocrinol. 2011;7(3):163-75. DOI: 10.1038/nrendo.2010.194

77. Taiwo Y, Levine J. Prostaglandins inhibit endogenous pain control mechanisms by blocking transmission at spinal noradrenergic synapses. The Journal of Neuroscience. 1988;8(4):1346-9. DOI: 10.1523/JNEUROSCI.08-04-01346.1988

78. Spicuzza L, Giembycz MA, Barnes PJ, Belvisi MG. Prostaglandin E2 suppression of acetylcholine release from parasympathetic nerves innervating guinea-pig trachea by interacting with prostanoid receptors of the EP3-subtype. British Journal of Pharmacology. 1998;123(6):1246-52. DOI: 10.1038/sj.bjp.0701720

79. Nakao K, Murase A, Ohshiro H, Okumura T, Taniguchi K, Murata Y, et al. CJ-023,423, a novel, potent and selective prostaglandin EP4 receptor antagonist with antihyperalgesic properties. J Pharmacol Exp Ther. 2007;322(2):686-94. DOI: 10.1124/jpet.107.122010

80. Rojas A, Gueorguieva P, Lelutiu N, Quan Y, Shaw R, Dingledine R. The prostaglandin EP1 receptor potentiates kainate receptor activation via a protein kinase C pathway and exacerbates status epilepticus. Neurobiol Dis. 2014;70:74-89.
DOI: 10.1016/j.nbd.2014.06.004

81. Furuyashiki T. Roles of dopamine and inflammation-related molecules in behavioral alterations caused by repeated stress. J Pharmacol Sci. 2012;120(2):63-9.
DOI: 10.1254/jphs.12r09cp

82. Furuyashiki T, Narumiya S. Roles of prostaglandin E receptors in stress responses. Curr Opin Pharmacol. 2009;9(1):31-8. DOI: 10.1016/j.coph.2008.12.010

83. K. Takeuchi. Prostaglandin EP receptors and their roles in mucosal protection and ulcer healing in the gastrointestinal tract. Adv Clin Chem 2010 Vol. 51 Pages 121-44
DOI: 10.1016/s0065-2423(10)51005-9

84. Araki H, Ukawa H, Sugawa Y, Yagi K, Suzuki K, Takeuchi K. The roles of prostaglandin E receptor subtypes in the cytoprotective action of prostaglandin E2 in rat stomach. Aliment Pharmacol Ther. 2000;14 Suppl 1:116-24. DOI: 10.1046/j.1365-2036.2000.014s1116.x

85. Jiang W, Jin Y, Zhang S, Ding Y, Huo K, Yang J, et al. PGE2 activates EP4 in subchondral bone osteoclasts to regulate osteoarthritis. Bone Res. 2022;10(1):27.
DOI: 10.1038/s41413-022-00201-4

86. Clark P, Rowland SE, Denis D, Mathieu MC, Stocco R, Poirier H, et al. MF498 [N-{[4-(5,9-Diethoxy-6-oxo-6,8-dihydro-7H-pyrrolo[3,4-g]quinolin-7-yl)-3-methylbenzyl]sulfonyl}-2-(2-methoxyphenyl)acetamide], a selective E prostanoid receptor 4 antagonist, relieves joint inflammation and pain in rodent models of rheumatoid and osteoarthritis. J Pharmacol Exp Ther. 2008;325(2):425-34. DOI: 10.1124/jpet.107.134510

87. Hedenberg-Magnusson B, Ernberg M, Alstergren P, Kopp S. Effect on prostaglandin E2 and leukotriene B4 levels by local administration of glucocorticoid in human masseter muscle myalgia. Acta Odontol Scand. 2002;60(1):29-36.
DOI: 10.1080/000163502753471970

88. Gu X, Xu J, Zhu L, Bryson T, Yang XP, Peterson E, et al. Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor. Circ Heart Fail. 2016;9(8).
DOI: 10.1161/CIRCHEARTFAILURE.116.003291

89. Maxwell DL, Bryson TD, Taube D, Xu J, Peterson E, Harding P. Deleterious effects of cardiomyocyte-specific prostaglandin E2 EP3 receptor overexpression on cardiac function after myocardial infarction. Life Sci. 2023;313:121277. DOI: 10.1016/j.lfs.2022.121277

90. Bärnthaler T, Maric J, Platzer W, Konya V, Theiler A, Hasenöhrl C, et al. The Role of PGE(2) in Alveolar Epithelial and Lung Microvascular Endothelial Crosstalk. Sci Rep. 2017;7(1):7923. DOI: 10.1038/s41598-017-08228-y

91. Theiler A, Konya V, Pasterk L, Maric J, Bärnthaler T, Lanz I, et al. The EP1/EP3 receptor agonist 17-pt-PGE2 acts as an EP4 receptor agonist on endothelial barrier function and in a model of LPS-induced pulmonary inflammation. Vascular Pharmacology. 2016;87:180-9.
DOI: 10.1016/j.vph.2016.09.008

92. Perrot CY, Herrera JL, Fournier-Goss AE, Komatsu M. Prostaglandin E2 breaks down pericyte-endothelial cell interaction via EP1 and EP4-dependent downregulation of pericyte N-cadherin, connexin-43, and R-Ras. Sci Rep. 2020;10(1):11186.
DOI: 10.1038/s41598-020-68019-w

93. Cipollone F, Fazia ML, Iezzi A, Cuccurullo C, De Cesare D, Ucchino S, et al. Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human. Arterioscler Thromb Vasc Biol. 2005;25(9):1925-31. https://doi.org/10.1161/01.ATV.0000177814.41505.41

94. Okazaki A, Hara J, Ohkura N, Fujimura M, Sakai T, Abo M, et al. Role of prostaglandin E(2) in bronchoconstriction-triggered cough response in guinea pigs. Pulm Pharmacol Ther. 2018;48:62-70. DOI: 10.1016/j.pupt.2017.09.003

95. Säfholm J, Manson ML, Bood J, Delin I, Orre AC, Bergman P, et al. Prostaglandin E2 inhibits mast cell-dependent bronchoconstriction in human small airways through the E prostanoid subtype 2 receptor. J Allergy Clin Immunol. 2015;136(5):1232-9.e1.
DOI: 10.1016/j.jaci.2015.04.002

96. Aronoff DM, Bergin IL, Lewis C, Goel D, O'Brien E, Peters-Golden M, et al. E-prostanoid 2 receptor signaling suppresses lung innate immunity against Streptococcus pneumoniae. Prostaglandins Other Lipid Mediat. 2012;98(1-2):23-30.
DOI: 10.1016/j.prostaglandins.2012.03.002

97. Zasłona Z, Okunishi K, Bourdonnay E, Domingo-Gonzalez R, Moore BB, Lukacs NW, et al. Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells. J Allergy Clin Immunol. 2014;133(2):379-87.
DOI: 10.1016/j.jaci.2013.07.037

98. Xiao L, Itani HA, Carmo LSd, Carver LS, Breyer RM, Harrison DG. Central EP3 (E Prostanoid 3) Receptors Mediate Salt-Sensitive Hypertension and Immune Activation. Hypertension. 2019;74(6):1507-15. DOI: 10.1161/HYPERTENSIONAHA.119.13850

99. Morimoto K, Shirata N, Taketomi Y, Tsuchiya S, Segi-Nishida E, Inazumi T, et al. Prostaglandin E2–EP3 Signaling Induces Inflammatory Swelling by Mast Cell Activation. The Journal of Immunology. 2014;192(3):1130-7. DOI: 10.4049/jimmunol.1300290

100. Chen X, Yin J, Xu Y, Qiu Z, Liu J, Chen X. Effect of selective inhibition or activation of PGE2 EP1 receptor on glomerulosclerosis. Mol Med Rep. 2020;22(4):2887-95.
DOI: 10.3892/mmr.2020.11353

101. Kresse JC, Mutsaers HAM, Jensen MS, Tingskov SJ, Madsen MG, Nejsum LN, et al. EP(1) receptor antagonism mitigates early and latestage renal fibrosis. Acta Physiol (Oxf). 2022;234(3):e13780. DOI: 10.1111/apha.13780

102. Scott G, Leopardi S, Printup S, Malhi N, Seiberg M, Lapoint R. Proteinase-activated receptor-2 stimulates prostaglandin production in keratinocytes: analysis of prostaglandin receptors on human melanocytes and effects of PGE2 and PGF2alpha on melanocyte dendricity. J Invest Dermatol. 2004;122(5):1214-24. DOI: 10.1111/j.0022-202X.2004.22516.x

103. Singh AK, Zajdel J, Mirrasekhian E, Almoosawi N, Frisch I, Klawonn AM, et al. Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain. J Clin Invest. 2017;127(4):1370-4. DOI: 10.1172/JCI90678

104. al-Zadjali KH, Imler MP, Ohia SE. Inhibitory effect of prostaglandins on dopamine release from the retina. Gen Pharmacol. 1994;25(2):289-96.
DOI: 10.1016/0306-3623(94)90057-4

105. Günther J, Schulte K, Wenzel D, Malinowska B, Schlicker E. Prostaglandins of the E series inhibit monoamine release via EP3 receptors: proof with the competitive EP3 receptor antagonist L-826,266. Naunyn Schmiedebergs Arch Pharmacol. 2010;381(1):21-31.
DOI: 10.1007/s00210-009-0478-9

106. Nakamura K, Katoh H, Ichikawa A, Negishi M. Inhibition of dopamine release by prostaglandin EP3 receptor via pertussis toxin-sensitive and -insensitive pathways in PC12 cells. J Neurochem. 1998;71(2):646-52. DOI: 10.1046/j.1471-4159.1998.71020646.x

107. G. O'Callaghan and A. Houston. Prostaglandin E2 and the EP receptors in malignancy: possible therapeutic targets? Br J Pharmacol 2015 Vol. 172 Issue 22 Pages 5239-50
DOI: 10.1111/bph.13331

(107)

Show all references Hide references