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Prostaglandin E2 (PGE2) suppresses natural killer cell function primarily through the PGE2 receptor EP4

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Abstract

The COX-2 product prostaglandin E2 (PGE2) contributes to the high metastatic capacity of breast tumors. Our published data indicate that inhibiting either PGE2 production or PGE2-mediated signaling through the PGE2 receptor EP4 reduces metastasis by a mechanism that requires natural killer (NK) cells. It is known that NK cell function is compromised by PGE2, but very little is known about the mechanism by which PGE2 affects NK effector activity. We now report the direct effects of PGE2 on the NK cell. Endogenous murine splenic NK cells express all four PGE2 receptors (EP1-4). We examined the role of EP receptors in three NK cell functions: migration, cytotoxicity, and cytokine release. Like PGE2, the EP4 agonist PGE1-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 PGE2, 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, PGE1-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 PGE2 production or preventing signaling through the EP4 receptor may prevent suppression of NK functions that are critical to the control of breast cancer metastasis.

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Acknowledgments

This study was supported by grant support from United States Department of Health and Human Services, United States Department of Defense, and the United States Department of Veteran Affairs.

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Authors and Affiliations

  1. Department of Pathology, School of Medicine, University of Maryland, Baltimore, MD, USA

    Dawn Holt, Namita Kundu & Amy Fulton

  2. Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA

    Xinrong Ma, Namita Kundu & Amy Fulton

  3. Baltimore Veterans Administration, Baltimore, MD, USA

    Amy Fulton

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  1. Dawn Holt
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  2. Xinrong Ma
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  3. Namita Kundu
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  4. Amy Fulton
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Correspondence to Amy Fulton.

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Holt, D., Ma, X., Kundu, N. et al. Prostaglandin E2 (PGE2) suppresses natural killer cell function primarily through the PGE2 receptor EP4. Cancer Immunol Immunother 60, 1577–1586 (2011). https://doi.org/10.1007/s00262-011-1064-9

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  • DOI: https://doi.org/10.1007/s00262-011-1064-9

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