PGE2-mediated immunosuppression by first trimester human decidual cells blocks activation of maternal leukocytes in the decidua with potential anti-trophoblast activity.
We have earlier shown that first trimester human decidual cells and decidual macrophages suppress T lymphocyte alloreactivity in an MHC-unrestricted manner by secreting PGE2, which blocks the generation of IL-2 receptors (IL-2R) and production of IL-2 by lymphocytes but does not interfere with the interaction between IL-2 and IL-2R or the lytic function of CTL, once generated. The present study examined whether these events constituted a physiological, immunoprotective mechanism in situ against the activation of maternal decidua-infiltrating leukocytes with potential anti-trophoblast cytocidal function. We examined (1) whether there was IL-2R expression, IL-2 production, or anti-trophoblast killer activity in short-term (0-3 day) cultures of collagenase-dispersed first trimester human decidua inclusive of leukocytes; (2) if not, whether any of these parameters could be stimulated in these cultures by blocking PGE2 synthesis with indomethacin, or neutralizing PGE2 with anti-PGE2 antibody; (3) whether exogenously added recombinant IL-2 in the presence or absence of indomethacin stimulated IL-2R expression or anti-trophoblast killer function in these cultures. IL-2R (as defined by Tac antigen) was measured in the whole cell population by a radioimmunoassay and further examined at the cellular level with radioautography. IL-2 production in culture supernatants was measured from the proliferative response (3HTdR uptake) of an IL-2-dependent (CTLL) cell line. Killer activity in fresh or cultured decidua-associated cells as well as PBL of normal or pregnant subjects was measured against 51Cr-labeled targets inclusive of autologous cytotrophoblast cells or long-term human trophoblast cell lines, K562 and Daudi cells. Results revealed a complete absence of IL-2R expression, IL-2 production, or anti-trophoblast killer activity in the untreated cultures of the decidua, but all these parameters were significantly stimulated in the presence of indomethacin or anti-PGE2 antibody. The indomethacin-stimulated killer cells had NK-like activity. Presence of high dose exogenous IL-2 alone in these cultures strongly stimulated IL-2R expression and anti-trophoblast killer function, which were augmented further in the additional presence of indomethacin. The resultant killer cells had LAK cell-like activity. These findings suggest that PGE2 secretion by first trimester human decidual cells blocks activation of maternal leukocytes in the decidua with potential anti-trophoblast killer function, by inhibiting IL-2 receptor generation and IL-2 production in situ.
Parhar
R S
RS
Department of Anatomy, University of Western Ontario, London, Canada.
Yagel
S
S
Lala
P K
PK
D003602:Cytotoxicity, Immunologic; D003656:Decidua / Q000276:immunology*; D015232:Dinoprostone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007376:Interleukin-2 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D011247:Pregnancy / Q000276:immunology*; D011263:Pregnancy Trimester, Third; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D014327:Trophoblasts / Q000276:immunology*
D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D015232:Dinoprostone; D007213:Indomethacin