{"id":3441,"date":"2026-04-24T21:49:02","date_gmt":"2026-04-24T21:49:02","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=3441"},"modified":"2026-08-25T21:54:30","modified_gmt":"2026-08-25T21:54:30","slug":"pge2-mediated-antagonism","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=3441","title":{"rendered":"PGE2-mediated antagonism"},"content":{"rendered":"\t\t
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PGE2-mediated antagonism and hormonal resistance, interrelated?<\/h2>\t\t\t\t<\/div>\n\t\t\t\t
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COVID-19, Long COVID, PGE2, imbalanced EP3 capacity and hormonal resistance, are they interrelated?<\/strong><\/p>\n\n

Research suggests that COVID-19, LC, and resistance phenomena such as type 2 diabetes (T2D) and obesity are interrelated 1<\/sup>. Both PGE2 and lack or excess of EP3 receptor expression have been reported to play crucial, yet incompletely understood, roles in insulin resistance or (T2D) and leptin resistance or obesity 2-7<\/sup>. We propose that the initial upregulation of PGE2 induced by SARS-CoV-2 infection may, in some individuals, persist beyond the acute phase, associated with altered EP3 receptor function. This imbalance may pre-exist and\/or be further amplified by sustained PGE2 elevation during infection. Such alterations in EP3 signaling could contribute to homeostatic dysregulation and presumed resistance phenomena, as discussed in the following sections.<\/p>\n\n

How could PGE2 antagonize other mediators, promoting resistance?<\/strong><\/p>\n\n

We previously noted that several PGE2 stimulating agents and are also antagonized by PGE2, including acetylcholine (ACh) 8<\/sup>, angiotensin II (Ang II) 9<\/sup>, AVP 10<\/sup>, serotonin (5-HT) 11<\/sup>, dopamine (DA) 12<\/sup>, fibroblast growth factor 23 (FGF23) 13<\/sup>, and interferon-gamma (IFN-\u03b3) 14<\/sup>. We identified several pathways by which PGE2 could antagonize the activity of other agents:<\/p>\n\n

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

    Stimulating autoantibodies and their class switching
    <\/strong>
    Upregulation of autoantibodies (aabs) of the immunoglobulin G (IgG) class to GPCRs has been observed in both COVID-19 15,16<\/sup>and LC patients 17,18<\/sup>. Animals experimentally infected with SARS-CoV-2 also generate functional aabs against GPCRs 19<\/sup>.<\/p>\n\n

    PGE2 has been shown to stimulate the production and class switching of autoantibodies from the immunoglobulin M (IgM) to IgG 20<\/sup> or IgE types 21<\/sup> 22,23<\/sup>, through the cAMP pathway (EP2\/EP4) 24<\/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 25,26<\/sup>.\u00a0

    Stimulating phosphorylation processes
    <\/strong>
    Another pathway involves stimulation of phosphorylation processes by PGE2 27-29<\/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 30<\/sup>. Phosphorylation has been reported to increase the binding of aabs by up to 2- or 7-fold 31,32<\/sup>.<\/p>\n\n

    Downregulation of the secretion of other agents

    <\/strong>PGE2 reportedly inhibits the secretion of other hormones through receptor EP3, such as: ACh 33<\/sup>, insulin 34<\/sup>and dopamine 35<\/sup>, noradrenaline 36<\/sup> and serotonin 36<\/sup>.<\/p>\n\n

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

    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 37<\/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 38<\/sup>. Many other monoamine receptors are Gi-, Gs-, or Gq-coupled as well.<\/p>\n\n

    1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Harding, J. L. et al.<\/em> The bidirectional association between diabetes and long-COVID-19 &#x2013; A systematic review. Diabetes Research and Clinical Practice<\/em> 195<\/strong> (2023). https:\/\/doi.org\/10.1016\/j.diabres.2022.110202<\/a><\/p>\n\n

    2\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Chan, P. C., Hsiao, F. C., Chang, H. M., Wabitsch, M. & Hsieh, P. S. Importance of adipocyte cyclooxygenase-2 and prostaglandin E2-prostaglandin E receptor 3 signaling in the development of obesity-induced adipose tissue inflammation and insulin resistance. Faseb j<\/em> 30<\/strong>, 2282-2297 (2016). https:\/\/doi.org\/10.1096\/fj.201500127<\/a><\/p>\n\n

    3\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Inazumi, T. et al.<\/em> Prostaglandin E<sub>2<\/sub>-EP4 Axis Promotes Lipolysis and Fibrosis in Adipose Tissue Leading to Ectopic Fat Deposition and Insulin Resistance. Cell Reports<\/em> 33<\/strong> (2020). https:\/\/doi.org\/10.1016\/j.celrep.2020.108265<\/a><\/p>\n\n

    4\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Henkel, J., Neusch\u00e4fer-Rube, F., Pathe-Neusch\u00e4fer-Rube, A. & P\u00fcschel, G. P. Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes. Hepatology<\/em> 50<\/strong>, 781-790 (2009). https:\/\/doi.org\/10.1002\/hep.23064<\/a><\/p>\n\n

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    37\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>\n\n

    38\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>\n\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\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"

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