Parhar R S, Yagel S, Lala P K
Department of Anatomy, University of Western Ontario, London, Canada.
Cell Immunol. 1989 Apr 15;120(1):61-74. doi: 10.1016/0008-8749(89)90174-3.
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.
我们之前已经表明，孕早期人蜕膜细胞和蜕膜巨噬细胞通过分泌前列腺素E2（PGE2）以MHC非限制性方式抑制T淋巴细胞同种异体反应性，PGE2可阻断白细胞介素-2受体（IL-2R）的生成以及淋巴细胞产生IL-2，但不干扰IL-2与IL-2R之间的相互作用或CTL一旦产生后的溶解功能。本研究探讨了这些事件是否构成一种生理性免疫保护机制，在原位针对具有潜在抗滋养层细胞杀伤功能的母体蜕膜浸润白细胞的激活。我们研究了：（1）在含白细胞的胶原酶分散的孕早期人蜕膜短期（0 - 3天）培养物中是否存在IL-2R表达、IL-2产生或抗滋养层细胞杀伤活性；（2）如果不存在，用吲哚美辛阻断PGE2合成或用抗PGE2抗体中和PGE2是否能在这些培养物中刺激这些参数中的任何一个；（3）在有或没有吲哚美辛存在的情况下，外源性添加重组IL-2是否能刺激这些培养物中的IL-2R表达或抗滋养层细胞杀伤功能。通过放射免疫测定法在全细胞群体中测量IL-2R（由Tac抗原定义），并通过放射自显影在细胞水平进一步检测。从IL-2依赖性（CTLL）细胞系的增殖反应（3HTdR摄取）测量培养上清液中的IL-2产生。针对包括自体细胞滋养层细胞或长期人滋养层细胞系、K562和Daudi细胞在内的51Cr标记靶标，测量新鲜或培养的蜕膜相关细胞以及正常或怀孕受试者外周血淋巴细胞中的杀伤活性。结果显示，在未处理的蜕膜培养物中完全不存在IL-2R表达、IL-2产生或抗滋养层细胞杀伤活性，但在吲哚美辛或抗PGE2抗体存在的情况下，所有这些参数均受到显著刺激。吲哚美辛刺激产生的杀伤细胞具有自然杀伤细胞样活性。在这些培养物中单独存在高剂量外源性IL-2强烈刺激IL-2R表达和抗滋养层细胞杀伤功能，在额外存在吲哚美辛的情况下进一步增强。产生的杀伤细胞具有淋巴因子激活的杀伤细胞样活性。这些发现表明，孕早期人蜕膜细胞分泌的PGE2通过抑制原位IL-2受体生成和IL-2产生，阻断了蜕膜中具有潜在抗滋养层细胞杀伤功能的母体白细胞的激活。
