• Login
    View Item 
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    •   UMB Digital Archive
    • School, Graduate
    • Theses and Dissertations All Schools
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of UMB Digital ArchiveCommunitiesPublication DateAuthorsTitlesSubjectsThis CollectionPublication DateAuthorsTitlesSubjects

    My Account

    LoginRegister

    Statistics

    Display statistics

    The Regulation of Natural Killer Cells through Prostaglandin E2 EP Receptors

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Find Full text
    Author
    Holt, Dawn M.
    Advisor
    Fulton, Amy M.
    Date
    2010
    Type
    dissertation
    
    Metadata
    Show full item record
    Abstract
    Natural Killer (NK) cell function is compromised by prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), but very little is known about the mechanism by which PGE<sub>2</sub> affects NK effector activity. Specifically, nothing is known regarding which PGE<sub>2</sub> receptor (EP1-4) mediates these effects. We have examined the role of individual EPs in regulating NK cells. Murine splenic or human NK cells express all four EP1-4 receptors. In endogenous NK cells from normal mice (N-NK), we show that activating all four NK-EP receptors with PGE<sub>2</sub> leads to less migration, reduced ability to lyse tumor targets, inhibited IFNγ secretion and decreased TNFα production. The ability of PGE<sub>2</sub> to inhibit N-NK cells is most likely through the EP4 receptor and, to a lesser degree, the EP2 receptor. Like PGE<sub>2</sub>, the EP4 agonist PGE1-OH blocked NK cell migration, inhibited cytotoxicity, and prevented cytokine secretion. The EP2 agonist, Butaprost, was able to inhibit cytotoxicity but did not blunt migration or effectively inhibit IFNγ secretion. In contrast to the inhibitory actions of PGE<sub>2</sub>, the EP1/EP3 agonist, Sulprostone, increased migration of N-NK cells. Thus, EP4 and EP1/3 may have opposing roles in regulating NK cells. NK cells from tumor bearing mice (T-NK) were compromised in many functions and showed reduced EP receptor expression. PGE<sub>2</sub> inhibits the potential of T-NK cells to migrate, exert cytotoxic effects, and secrete IFNγ. This ability of PGE<sub>2</sub> to inhibit NK cells from tumor bearing mice is mimicked by EP2 and EP4 agonists and, therefore most likely through EP2 and EP4 receptors. T-NK cells stimulated with PGE<sub>2</sub>, EP2 agonist (Butaprost), and EP4 agonist (PGE1-OH) were more sensitive to inhibition compared to N-NK cells. In contrast to the inhibitory effects of PGE<sub>2</sub> on cytotoxicity, and IFNγ production, TNFα secretion was actually induced in T-NK. Thus, PGE<sub>2</sub> inhibits TNFα secretion from N-NK, and further increases the constitutively high TNFα secretion from T-NK. Taken together our results show that tumor-derived PGE<sub>2</sub> is able to suppress many NK functions that are critical to tumor control and much of this inhibition is mediated through the EP4 receptor on NK cells. These data, combined with our published studies showing that tumor-expressed EP4 promotes metastasis, support the rationale to develop more effective EP antagonists as novel therapeutic agents.
    Description
    University of Maryland in Baltimore. Pathology. Ph.D. 2010
    Keyword
    EP receptors
    prostaglandin E2
    Breast--Cancer
    Dinoprostone
    Killer Cells, Natural
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/907
    Collections
    Theses and Dissertations All Schools
    Theses and Dissertations School of Medicine

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Quick Guide | Policies | Contact Us | UMB Health Sciences & Human Services Library
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.