{"id":5051,"date":"2026-08-23T19:36:19","date_gmt":"2026-08-23T19:36:19","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=5051"},"modified":"2026-08-26T05:55:45","modified_gmt":"2026-08-26T05:55:45","slug":"pge2-antagonism-and-resistance","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=5051","title":{"rendered":"PGE2 antagonism and resistance"},"content":{"rendered":"\t\t
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PGE2's reported antagonizing strategies <\/h2>\t\t\t\t<\/div>\n\t\t\t\t
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How could PGE2 antagonize other mediators, promoting resistance?<\/h3>

Diverse PGE2 stimulating agents and are antagonized by PGE2, including acetylcholine (ACh) 1<\/sup>, angiotensin II (Ang II) 2<\/sup>, AVP 3<\/sup>, serotonin (5-HT) 4<\/sup>, dopamine (DA) 5<\/sup>, fibroblast growth factor 23 (FGF23) 6<\/sup>, and interferon-gamma (IFN-\u03b3) 7<\/sup>. We identified several pathways by which PGE2 could antagonize the activity of other agents:<\/p>

  1. Stimulating functional autoantibodies (aabs) to the receptors of other agents and their class switching (through EP2\/EP4)<\/li>
  2. Stimulating phosphorylation of their receptors, possibly attracting autoantibodies (through EP1)<\/li>
  3. Downregulation of their secretion (through EP3)<\/li>
  4. Indirect functional antagonism of GPCRs through shared subcellular pathways<\/li><\/ol>

    _______________________________________________________________________________________________________________________________________________<\/p>

    1. Stimulating autoantibodies and their class switching<\/strong><\/p>

    Upregulation of autoantibodies (aabs) of the immunoglobulin G (IgG) class to GPCRs has been observed in both COVID-19 8,9<\/sup> and LC patients 10,11<\/sup>. Animals experimentally infected with SARS-CoV-2 also generate functional aabs against GPCRs 12<\/sup>.<\/p>

    PGE2 has been shown to stimulate the production and class switching of autoantibodies from the immunoglobulin M (IgM) to IgG 13<\/sup> or IgE types 14<\/sup> 15,16<\/sup>, through the cAMP pathway (EP2\/EP4) 17<\/sup>. Aabs can modulate the binding of true ligands. We suggest that PGE2 may hinder ligand binding in COVID-19 and LC through aab production 18,19<\/sup>.\u00a0<\/p>

    2. Stimulating phosphorylation processes<\/strong>

    <\/strong>Another pathway involves stimulation of phosphorylation processes by PGE2 20-22<\/sup>. We suggest that PGE2 could interfere with receptor binding of specific compounds by promoting receptor or ligand phosphorylation, including via the EP1 PKC pathway 23<\/sup>. Phosphorylation has been reported to increase the binding of aabs by up to 2- or 7-fold 24,25<\/sup>.<\/p>

    3. Downregulation of the secretion of other agents<\/strong><\/p>

    PGE2 reportedly inhibits the secretion of other hormones through receptor EP3, such as: ACh 26<\/sup>, insulin 27<\/sup> and dopamine 28<\/sup>, noradrenaline 29<\/sup> and serotonin 29<\/sup>.<\/p>

    4. Indirect functional antagonism of GPCR-ligands through shared subcellular pathways<\/strong><\/p>

    In section 3, it has been discussed that EP receptors belong to the class of the G-protein coupled receptors (GPCRs). Reportedly, PGE2 dominance could interfere with the signaling of other GPCR-binding hormones that use the same downstream signaling pathways 30<\/sup>. GPCR signaling depends on a finite pool of Gi or Gs proteins and other downstream second messengers. The EP3 receptor is Gi-coupled, and EP2 and EP4 are Gscoupled 31<\/sup>. Many other monoamine receptors are Gi-, Gs-, or Gq-coupled as well.<\/p>

    1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Reinheimer, T., Harnack, E., Racke, K. & Wessler, I. Prostanoid receptors of the EP3 subtype mediate inhibition of evoked [3H]acetylcholine release from isolated human bronchi. Br J Pharmacol<\/em> 125<\/strong>, 271-276 (1998). https:\/\/doi.org\/10.1038\/sj.bjp.0702057<\/a><\/p>

    2\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Broughton Pipkin, F., Hunter, J. C., Turner, S. R. & O’Brien, P. M. Prostaglandin E2 attenuates the pressor response to angiotensin II in pregnant subjects but not in nonpregnant subjects. Am J Obstet Gynecol<\/em> 142<\/strong>, 168-176 (1982). https:\/\/doi.org\/10.1016\/s0002-9378(16)32331-6<\/a><\/p>

    3\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 H\u00e9bert, R. L., Jacobson, H. R. & Breyer, M. D. PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation. Am J Physiol<\/em> 259<\/strong>, F318-325 (1990). https:\/\/doi.org\/10.1152\/ajprenal.1990.259.2.F318<\/a><\/p>

    4\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Singh, A. K. et al.<\/em> Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain. J Clin Invest<\/em> 127<\/strong>, 1370-1374 (2017). https:\/\/doi.org\/10.1172\/jci90678<\/a><\/p>

    5\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Tanaka, Y. et al.<\/em> Prostaglandin E receptor EP1 enhances GABA-mediated inhibition of dopaminergic neurons in the substantia nigra pars compacta and regulates dopamine level in the dorsal striatum. Eur J Neurosci<\/em> 30<\/strong>, 2338-2346 (2009). https:\/\/doi.org\/10.1111\/j.1460-9568.2009.07021.x<\/a><\/p>

    6\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Baum, M., Syal, A., Quigley, R. & Seikaly, M. Role of prostaglandins in the pathogenesis of X-linked hypophosphatemia. Pediatr Nephrol<\/em> 21<\/strong>, 1067-1074 (2006). https:\/\/doi.org\/10.1007\/s00467-006-0126-2<\/a><\/p>

    7\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Mathieu, M. C. et al.<\/em> Mutual antagonistic relationship between prostaglandin E(2) and IFN-gamma: Implications for rheumatoid arthritis. Eur J Immunol<\/em> 38<\/strong>, 1900-1912 (2008). https:\/\/doi.org\/10.1002\/eji.200838170<\/a><\/p>

    8\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Sacchi, M. C. et al.<\/em> SARS-CoV-2 infection as a trigger of autoimmune response. Clin Transl Sci<\/em> 14<\/strong>, 898-907 (2021). https:\/\/doi.org\/10.1111\/cts.12953<\/a><\/p>

    9\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Geanes, E. S., McLennan, R., LeMaster, C. & Bradley, T. Autoantibodies to ACE2 and immune molecules are associated with COVID-19 disease severity. Communications Medicine<\/em> 4<\/strong>, 47 (2024). https:\/\/doi.org\/10.1038\/s43856-024-00477-z<\/a><\/p>

    10\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Talwar, S., Harker, J. A., Openshaw, P. J. M. & Thwaites, R. S. Autoimmunity in long COVID. Journal of Allergy and Clinical Immunology<\/em> 155<\/strong>, 1082-1094 (2025). https:\/\/doi.org\/https:\/\/doi.org\/10.1016\/j.jaci.2025.02.005<\/a><\/p>

    11\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Sotzny, F. et al.<\/em> Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Frontiers in Immunology<\/em> Volume 13 – 2022<\/strong> (2022). https:\/\/doi.org\/10.3389\/fimmu.2022.981532<\/a><\/p>

    12\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Wallukat, G., Wernike, K., Bachamanda Somesh, D., Mettenleiter, T. C. & M\u00fcller, J. Animals Experimentally Infected with SARS-CoV-2 Generate Functional Autoantibodies against G-Protein-Coupled Receptors. Biomedicines<\/em> 11<\/strong> (2023). https:\/\/doi.org\/10.3390\/biomedicines11102668<\/a><\/p>

    13\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Stein, S. H. & Phipps, R. P. Antigen-specific IGG2A production in response to prostaglandin E2, immune complexes, and IFN-gamma. The Journal of Immunology<\/em> 147<\/strong>, 2500-2506 (1991). https:\/\/doi.org\/10.4049\/jimmunol.147.8.2500<\/a><\/p>

    14\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Fedyk, E. R. & Phipps, R. P. Prostaglandin E2 receptors of the EP2 and EP4 subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells. Proc Natl Acad Sci U S A<\/em> 93<\/strong>, 10978-10983 (1996). https:\/\/doi.org\/10.1073\/pnas.93.20.10978<\/a><\/p>

    15\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ishihara, Y. et al.<\/em> Regulation of Immunoglobulin G2 Production by Prostaglandin E<sub>2<\/sub> and Platelet-Activating Factor. Infection and Immunity<\/em> 68<\/strong>, 1563-1568 (2000). https:\/\/doi.org\/doi:10.1128\/iai.68.3.1563-1568.2000<\/a><\/p>

    16\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Roper, R. L. & Phipps, R. P. Prostaglandin E2 and cAMP inhibit B lymphocyte activation and simultaneously promote IgE and IgG1 synthesis. J Immunol<\/em> 149<\/strong>, 2984-2991 (1992).<\/p>

    17\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Tsuge, K., Inazumi, T., Shimamoto, A. & Sugimoto, Y. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int Immunol<\/em> 31<\/strong>, 597-606 (2019). https:\/\/doi.org\/10.1093\/intimm\/dxz021<\/a><\/p>

    18\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Ludwig, R. J. et al.<\/em> Mechanisms of Autoantibody-Induced Pathology. Frontiers in Immunology<\/em> Volume 8 – 2017<\/strong> (2017). https:\/\/doi.org\/10.3389\/fimmu.2017.00603<\/a><\/p>

    19\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Meyer, C. & Heidecke, H. Antibodies Against GPCR. Front Biosci (Landmark Ed)<\/em> 23<\/strong>, 2177-2194 (2018). https:\/\/doi.org\/10.2741\/4698<\/a><\/p>

    20\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Lone, A. M. & Task\u00e9n, K. Phosphoproteomics-Based Characterization of Prostaglandin E2 Signaling in T Cells. Molecular Pharmacology<\/em> 99<\/strong>, 370-382 (2021). https:\/\/doi.org\/https:\/\/doi.org\/10.1124\/molpharm.120.000170<\/a><\/p>

    21\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Lenz, K. M., Wright, C. L., Martin, R. C. & McCarthy, M. M. Prostaglandin E2 Regulates AMPA Receptor Phosphorylation and Promotes Membrane Insertion in Preoptic Area Neurons and Glia during Sexual Differentiation. PLOS ONE<\/em> 6<\/strong>, e18500 (2011). https:\/\/doi.org\/10.1371\/journal.pone.0018500<\/a><\/p>

    22\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Cao, L. L., Guan, P. P., Liang, Y. Y., Huang, X. S. & Wang, P. Cyclooxygenase-2 is Essential for Mediating the Effects of Calcium Ions on Stimulating Phosphorylation of Tau at the Sites of Ser 396 and Ser 404. J Alzheimers Dis<\/em> 68<\/strong>, 1095-1111 (2019). https:\/\/doi.org\/10.3233\/jad-181066<\/a><\/p>

    23\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bai, X. et al.<\/em> Prostaglandin E2 receptor EP1-mediated phosphorylation of focal adhesion kinase enhances cell adhesion and migration in hepatocellular carcinoma cells. Int J Oncol<\/em> 42<\/strong>, 1833-1841 (2013). https:\/\/doi.org\/10.3892\/ijo.2013.1859<\/a><\/p>

    24\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Stetler, D. A. & Jacob, S. T. Phosphorylation of RNA polymerase I augments its interaction with autoantibodies of systemic lupus erythematosus patients. J Biol Chem<\/em> 259<\/strong>, 13629-13632 (1984).<\/p>

    25\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Pfeifle, J., Anderer, F. A. & Franke, M. Multiple phosphorylation of human SS-B\/LA autoantigen and its effect on poly(U) and autoantibody binding. Biochim Biophys Acta<\/em> 928<\/strong>, 217-226 (1987). https:\/\/doi.org\/10.1016\/0167-4889(87)90124-8<\/a><\/p>

    26\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Clarke, D. L., Giembycz, M. A., Patel, H. J. & Belvisi, M. G. E-Ring 8-isoprostanes inhibit ACh release from parasympathetic nerves innervating guinea-pig trachea through agonism of prostanoid receptors of the EP3-subtype. British Journal of Pharmacology<\/em> 141<\/strong>, 600-609 (2004). https:\/\/doi.org\/https:\/\/doi.org\/10.1038\/sj.bjp.0705648<\/a><\/p>

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    28\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 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<\/em> 71<\/strong>, 646-652 (1998). https:\/\/doi.org\/10.1046\/j.1471-4159.1998.71020646.x<\/a><\/p>

    29\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 G\u00fcnther, 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<\/em> 381<\/strong>, 21-31 (2010). https:\/\/doi.org\/10.1007\/s00210-009-0478-9<\/a><\/p>

    30\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Werry, T. D., Wilkinson, G. F. & Willars, G. B. Mechanisms of cross-talk between G-protein-coupled receptors resulting in enhanced release of intracellular Ca2+. Biochem J<\/em> 374<\/strong>, 281-296 (2003). https:\/\/doi.org\/10.1042\/bj20030312<\/a><\/p>

    31\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Biringer, R. G. A Review of Prostanoid Receptors: Expression, Characterization, Regulation, and Mechanism of Action. J Cell Commun Signal<\/em> 15<\/strong>, 155-184 (2021). https:\/\/doi.org\/10.1007\/s12079-020-00585-0<\/a><\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t

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    PGE2’s reported antagonizing strategies How could PGE2 antagonize other mediators, promoting resistance? Diverse PGE2 stimulating agents and are antagonized by […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"site-sidebar-layout":"no-sidebar","site-content-layout":"","ast-site-content-layout":"full-width-container","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"disabled","footer-sml-layout":"","ast-disable-related-posts":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"footnotes":""},"class_list":["post-5051","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/5051","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=5051"}],"version-history":[{"count":32,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/5051\/revisions"}],"predecessor-version":[{"id":5954,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/5051\/revisions\/5954"}],"wp:attachment":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=5051"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}