title: Prostaglandin E(2) (PGE          (2)) suppresses natural killer cell function primarily through the PGE(2) receptor EP4.
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.
authors.affiliation: Department of Pathology, School of Medicine, University of Maryland, Baltimore, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Holt
authors.forename: Xinrong
authors.initials: X
authors.lastname: Ma
authors.forename: Namita
authors.initials: N
authors.lastname: Kundu
authors.forename: Amy
authors.initials: A
authors.lastname: Fulton
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D007694:Killer Cells, Natural / Q000276:immunology*; D016399:Lymphoma, T-Cell / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000276:immunology*
chemical_list: D058309:Receptors, Prostaglandin E, EP4 Subtype; D015232:Dinoprostone