Prostaglandin E(2) (PGE (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4
Related Experiment Video
Updated: May 31, 2026
Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
Dawn Holt1, Xinrong Ma, Namita Kundu
1Department of Pathology, School of Medicine, University of Maryland, Baltimore, USA.
Abstract:
The COX-2 product prostaglandin E(2) (PGE(2)) contributes to the high metastatic capacity of breast tumors. Our published data indicate that inhibiting either PGE(2) production or PGE(2)-mediated signaling through the PGE(2) receptor EP4 reduces metastasis by a mechanism that requires natural killer (NK) cells. It is known that NK cell function is compromised by PGE(2), but very little is known about the mechanism by which PGE(2) affects NK effector activity. We now report the direct effects of PGE(2) on the NK cell. Endogenous murine splenic NK cells express all four PGE(2) receptors (EP1-4). We examined the role of EP receptors in three NK cell functions: migration, cytotoxicity, and cytokine release. Like PGE(2), the EP4 agonist PGE(1)-OH blocked NK cell migration to FBS and to four chemokines (ITAC, MIP-1α, SDF-1α, and CCL21). The EP2 agonist, Butaprost, inhibited migration to specific chemokines but not in response to FBS. In contrast to the inhibitory actions of PGE(2), the EP1/EP3 agonist Sulprostone increased migration. Unlike the opposing effects of EP4 vs. EP1/EP3 on migration, agonists of each EP receptor were uniformly inhibiting to NK-mediated cytotoxicity. The EP4 agonist, PGE(1)-OH, inhibited IFNγ production from NK cells. Agonists for EP1, EP2, and EP3 were not as effective at inhibiting IFNγ. Agonists of EP1, EP2, and EP4 all inhibited TNFα; EP4 agonists were the most potent. Thus, the EP4 receptor consistently contributed to loss of function. These results, taken together, support a mechanism whereby inhibiting PGE(2) production or preventing signaling through the EP4 receptor may prevent suppression of NK functions that are critical to the control of breast cancer metastasis.
Insights
Prostaglandin E2 (PGE2) promotes breast cancer metastasis by suppressing natural killer (NK) cell function. Targeting the EP4 receptor on NK cells can restore their anti-tumor activity, offering a new therapeutic strategy.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Prostaglandin E2 (PGE2), a product of COX-2, is implicated in breast tumor metastasis.
- PGE2 compromises natural killer (NK) cell function, but the precise mechanisms are not fully understood.
- Previous studies show that inhibiting PGE2 or its receptor EP4 reduces metastasis, requiring NK cells.
Purpose of the Study:
- To investigate the direct effects of PGE2 and its receptor subtypes (EP1-4) on NK cell functions.
- To elucidate the role of EP receptors in NK cell migration, cytotoxicity, and cytokine release.
- To determine the specific EP receptor subtype mediating PGE2's suppressive effects on NK cells.
Main Methods:
- Murine splenic NK cells were utilized to assess the expression of all four PGE2 receptors (EP1-4).
- The impact of PGE2 and specific EP receptor agonists (PGE(1)-OH for EP4, Butaprost for EP2, Sulprostone for EP1/EP3) on NK cell migration, cytotoxicity, and cytokine release (IFNγ, TNFα) was examined.
- Functional assays included migration to FBS and chemokines, cytotoxicity assays, and cytokine production measurements.
Main Results:
- PGE2 and the EP4 agonist PGE(1)-OH inhibited NK cell migration.
- The EP2 agonist Butaprost showed partial inhibition of chemokine-induced migration, while the EP1/EP3 agonist Sulprostone enhanced migration.
- All EP receptor agonists uniformly inhibited NK cell-mediated cytotoxicity.
- The EP4 agonist significantly inhibited IFNγ production, and EP1, EP2, and EP4 agonists inhibited TNFα production, with EP4 being most potent.
Conclusions:
- The EP4 receptor consistently contributes to the suppression of NK cell functions.
- Inhibiting PGE2 production or blocking EP4 receptor signaling can restore NK cell activity.
- These findings support a mechanism where targeting PGE2/EP4 signaling may enhance NK cell-mediated control of breast cancer metastasis.
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