Published data on PGE2, immune cells, and cytokines

The following findings from the literature are relevant to the proposed relationship between PGE2 signaling, immune-cell function, cytokine profiles, and fatigue in Long COVID.

Cytokines and clinical subphenotypes

• Cytokine subphenotypes have been identified in Long COVID and shown to correlate with distinct symptom subphenotypes.¹
• Research comparing fatigued and non-fatigued Long COVID patients has identified differences in monocyte-related immune profiles.²
• Immunological profiling has reported overall low-grade inflammation, T-lymphocyte senescence, and increased monocyte activation, with monocyte activation correlating with increasing fatigue severity.²

Mitochondrial dysfunction, fatigue, and EP2 signaling

• In aged mice, blockade of the PGE2 receptor EP2 improved mitochondrial function in alveolar macrophages.³

Monocytes and PGE2 signaling

• PGE2 may modulate immune responses by regulating the expression of specific adhesion molecules on monocytes through EP2 and EP4 receptors.⁴

Monocytes as a source of PGE2

• Monocytes have been identified as an important source of PGE2. In one study, abnormally high PGE2 production by monocytes was associated with reduced NK-cell activity, while removal of monocytes from PBMCs restored NK- and LAK-cell activity to near-normal levels in patients.⁵
• Cortisol, 6-methylprednisolone, and dexamethasone suppressed LPS-induced PGE2 biosynthesis in both whole blood and isolated monocytes in vitro, at concentrations comparable to those associated with their anti-inflammatory effects in vivo.⁶

Monocyte-derived dendritic cells, T-cell polarization, and PGE2

• Cooperative stimulation of EP2 and EP4 receptors by PGE2 was reported to promote maturation of monocyte-derived dendritic cells (MoDCs) while inhibiting LPS-induced cytokine production. Under these conditions, the mature MoDCs preferentially induced Th2 polarization, suggesting a role for EP2 and EP4 signaling in determining Th1/Th2 development of naïve T cells.⁷

PGE2 and regulation of immune responses

• PGE2 can modulate multiple components of the immune response. It has been reported to suppress effector functions of macrophages and neutrophils, as well as Th1-, CTL-, and NK-cell-mediated type 1 immunity, while promoting Th2, Th17, and regulatory T-cell responses.⁸
• PGE2 has also been reported to stimulate EP4 receptors and promote Th1 differentiation and Th17 expansion.⁹
• Other findings suggest that PGE2 can suppress both Th1- and Th2-polarized antigen-specific human T-cell responses through a cAMP-dependent EP2/EP4 pathway.¹⁰
• Elevated PGE2 levels have additionally been associated with promotion of type 2 Th responses.¹¹

References

1             Sidiropoulou, C. et al. Long-term immune and epigenetic dysregulation following COVID-19. Clin Immunol 283, 110656 (2026). https://doi.org/10.1016/j.clim.2025.110656

2             Berentschot, J. C. et al. Immunological profiling in long COVID: overall low grade inflammation and T-lymphocyte senescence and increased monocyte activation correlating with increasing fatigue severity. Frontiers in Immunology Volume 14 – 2023 (2023). https://doi.org/10.3389/fimmu.2023.1254899

3             Chen, J. et al. Age-induced prostaglandin E2 impairs mitochondrial fitness and increases mortality to influenza infection. Nature Communications 13, 6759 (2022). https://doi.org/10.1038/s41467-022-34593-y

4             Takahashi, H. K. et al. Prostaglandin E(2) inhibits IL-18-induced ICAM-1 and B7.2 expression through EP2/EP4 receptors in human peripheral blood mononuclear cells. J Immunol 168, 4446-4454 (2002). https://doi.org/10.4049/jimmunol.168.9.4446

5             Baxevanis, C. N. et al. Elevated prostaglandin E2 production by monocytes is responsible for the depressed levels of natural killer and lymphokine-activated killer cell function in patients with breast cancer. Cancer 72, 491-501 (1993). https://doi.org/10.1002/1097-0142(19930715)72:2<491::aid-cncr2820720227>3.0.co;2-1

6             Santini, G. et al. The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids. Clin Pharmacol Ther 70, 475-483 (2001). https://doi.org/10.1067/mcp.2001.119213

7             Kubo, S. et al. E-prostanoid (EP)2/EP4 receptor-dependent maturation of human monocyte-derived dendritic cells and induction of helper T2 polarization. J Pharmacol Exp Ther 309, 1213-1220 (2004). https://doi.org/10.1124/jpet.103.062646

8             Kalinski, P. Regulation of immune responses by prostaglandin E2. J Immunol 188, 21-28 (2012). https://doi.org/10.4049/jimmunol.1101029

9             Chen, Q. et al. A novel antagonist of the prostaglandin E(2) EP(4) receptor inhibits Th1 differentiation and Th17 expansion and is orally active in arthritis models. Br J Pharmacol 160, 292-310 (2010). https://doi.org/10.1111/j.1476-5381.2010.00647.x

10           Okano, M. et al. E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2. Immunology 118, 343-352 (2006). https://doi.org/10.1111/j.1365-2567.2006.02376.x

11           Kaliński, P., Hilkens, C. M., Snijders, A., Snijdewint, F. G. & Kapsenberg, M. L. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol 159, 28-35 (1997).

12           Kawahara, K., Hohjoh, H., Inazumi, T., Tsuchiya, S. & Sugimoto, Y. Prostaglandin E2-induced inflammation: Relevance of prostaglandin E receptors. Biochimica et Biophysica Acta (BBA) – Molecular and Cell Biology of Lipids 1851, 414-421 (2015). https://doi.org/https://doi.org/10.1016/j.bbalip.2014.07.008

13           Wang, X.-s., Sze Wing, S., Kwok Ho, Y. & Lau, H. Y. A. Functional characterization of human mast cells cultured from adult peripheral blood. International Immunopharmacology 6, 839-847 (2006). https://doi.org/https://doi.org/10.1016/j.intimp.2005.12.004

14           Wang, X. S. & Lau, H. Y. Prostaglandin E potentiates the immunologically stimulated histamine release from human peripheral blood-derived mast cells through EP1/EP3 receptors. Allergy 61, 503-506 (2006). https://doi.org/10.1111/j.1398-9995.2006.01043.x