How could PGE2 antagonize other mediators, promoting resistance?

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

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

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1. Stimulating autoantibodies and their class switching

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

PGE2 has been shown to stimulate the production and class switching of autoantibodies from the immunoglobulin M (IgM) to IgG ¹³ or IgE types ^{14 15,16}, through the cAMP pathway (EP2/EP4) ¹⁷. 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. 

2. Stimulating phosphorylation processes

Another pathway involves stimulation of phosphorylation processes by PGE2 ^20-22. 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. Phosphorylation has been reported to increase the binding of aabs by up to 2- or 7-fold ^24,25.

3. Downregulation of the secretion of other agents

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

4. Indirect functional antagonism of GPCR-ligands through shared subcellular pathways

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. 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. Many other monoamine receptors are Gi-, Gs-, or Gq-coupled as well.

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