{"id":5751,"date":"2026-08-25T21:12:10","date_gmt":"2026-08-25T21:12:10","guid":{"rendered":"https:\/\/pge2-hypothesis.com\/?page_id=5751"},"modified":"2026-09-29T23:08:05","modified_gmt":"2026-09-29T23:08:05","slug":"potential-risks-of-decreasing-pge2","status":"publish","type":"page","link":"https:\/\/pge2-hypothesis.com\/?page_id=5751","title":{"rendered":"Potential risks of decreasing PGE2"},"content":{"rendered":"\t\t
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Systemic PGE2 reduction carries potential risks<\/h2>\t\t\t\t<\/div>\n\t\t\t\t
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PGE2 downregulation may increase EP-receptor imbalance in some patients (!)<\/h3>

The following information is particularly important for the clinical implications of this hypothesis: systemic reduction of PGE2 may affect the balance of EP-receptor expression. PGE2 upregulation is associated with reduced EP3 expression and, in many cases, increased expression of EP1, EP2 and EP4.\u00b9\u207b\u00b3 With PGE2 downregulation, the opposite could be expected: EP3 expression may increase, while EP1, EP2 and EP4 expression may decrease. This could be beneficial for patients with an \u201cEP3-down\u201d profile, but potentially detrimental for those with an \u201cEP3-up\u201d profile, as the imbalance could be further amplified if EP3 expression increases even more.<\/p>\t\t\t\t\t\t\t\t<\/div>\n\t\t\t\t

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A new perspective on NSAID side effects<\/h3>

NSAIDs reduce PGE2 production by inhibiting the enzyme COX-2, which also synthesizes other prostaglandins. They are known to cause adverse effects in some patients. Their lack of sufficient selectivity may contribute to this, but we hypothesize that a major factor may be that their effects on EP-receptor expression can be counterproductive in some patients.<\/p>

The hypothesis that the \u201cEP3-up\u201d category may be particularly susceptible is supported by the fact that serious NSAID-related adverse effects are often cardiovascular or renal, processes that may be strongly influenced by EP3 signaling. EP4 activity, which is relatively reduced in the \u201cEP3-up\u201d profile, provides protection against gastric ulcers,\u2074 another well-known complication of NSAID use that might therefore be more likely in patients with an \u201cEP3-up\u201d profile.<\/p>

See for more information and references the page: “On NSAID side effects”<\/a><\/p>

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1\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Haddad, A. et al.<\/em> Prostaglandin EP1 Receptor Down-regulates Expression of Cyclooxygenase-2 by Facilitating Its Proteasomal Degradation. Journal of Biological Chemistry<\/em> 287, 17214-17223 (2012). https:\/\/doi.org\/https:\/\/doi.org\/10.1074\/jbc.M111.304220<\/a><\/p>

2\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bonfill-Teixidor, E., Otxoa-de-Amezaga, A., Font-Nieves, M., Sans-Fons, M. G. & Planas, A. M. Differential expression of E-type prostanoid receptors 2 and 4 in microglia stimulated with lipopolysaccharide. J Neuroinflammation<\/em> 14, 3 (2017). https:\/\/doi.org\/10.1186\/s12974-016-0780-7<\/a><\/p>

3\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Bilson, H. A., Mitchell, D. L. & Ashby, B. Human prostaglandin EP3 receptor isoforms show different agonist-induced internalization patterns. FEBS Lett<\/em> 572, 271-275 (2004). https:\/\/doi.org\/10.1016\/j.febslet.2004.06.089<\/a><\/p>

4\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0\u00a0 Takeuchi, K. & Amagase, K. Roles of Cyclooxygenase, Prostaglandin E2 and EP Receptors in Mucosal Protection and Ulcer Healing in the Gastrointestinal Tract. Curr Pharm Des<\/em> 24, 2002-2011 (2018). https:\/\/doi.org\/10.2174\/1381612824666180629111227<\/a><\/p>

References<\/p>

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Systemic PGE2 reduction carries potential risks \u00a0 PGE2 downregulation may increase EP-receptor imbalance in some patients (!) The following information […]<\/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-5751","page","type-page","status-publish","hentry"],"_links":{"self":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/5751","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=5751"}],"version-history":[{"count":89,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/5751\/revisions"}],"predecessor-version":[{"id":6665,"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=\/wp\/v2\/pages\/5751\/revisions\/6665"}],"wp:attachment":[{"href":"https:\/\/pge2-hypothesis.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=5751"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}