Alleva D G, Burger C J, Elgert K D
Department of Biology, Virginia Polytechnic Institute and State University, Blacksburg 24061.
Immunopharmacology. 1993 May-Jun;25(3):215-27. doi: 10.1016/0162-3109(93)90050-z.
Tumor growth enhances macrophage (M phi) suppressor activity by causing M phi to increase synthesis of inhibitory molecules such as prostaglandin E2 (PGE2) or decreasing their expression of up-regulatory molecules such as the class II MHC protein Ia. Although these tumor-induced changes are correlated, it is unknown whether tumor-bearing host (TBH) Ia- M phi become more suppressive by increasing their PGE2 synthesis. To assess the role of PGE2 in tumor-induced Ia- M phi-mediated suppression of CD4+ T-cell alloreactivity, unseparated (Ia(+)-enriched) or Ia(+)-depleted (Ia-) populations of murine normal host (NH) or TBH splenic M phi were added to mixed lymphocyte reaction (MLR) cultures. NH or TBH Ia- M phi were significantly more suppressive than their respective unseparated populations, and TBH Ia- M phi were more suppressive than their NH counterparts. When PGE2 production was blocked with indomethacin, TBH Ia- M phi-mediated suppression was reduced more than suppression mediated by all other M phi populations. A PGE2-specific ELISA showed more PGE2 in Ia- M phi-containing cultures than in those with whole M phi and more in cultures containing TBH Ia- M phi than in their NH counterparts. Because interferon-gamma (IFN-gamma) is a potent M phi activation molecule that regulates both Ia expression and PGE2 production, the effects of IFN-gamma on tumor-induced Ia- M phi-mediated suppression were investigated. Exogenous IFN-gamma reduced suppression mediated by all M phi populations except NH unseparated M phi. IFN-gamma suppressed alloreactivity without M phi or with NH unseparated M phi. Suppression mediated by NH or TBH Ia-, and TBH unseparated M phi was also reduced when M phi were pre-incubated with IFN-gamma before their addition to MLR cultures. IFN-gamma addition did not block Ia- M phi-mediated suppression by decreasing M phi PGE2 production. In fact, IFN-gamma addition increased PGE2 production two-fold in MLR cultures. However, IFN-gamma partly reduced suppression mediated by exogenous PGE2 added to M phi-depleted cultures. Cytofluorometric analysis showed that IFN-gamma increased the percentage of Ia+ M phi in NH and TBH Ia- M phi populations. Blocking TNF-alpha activity with anti-TNF-alpha antibodies caused IFN-gamma to suppress alloreactivity in all M phi-added cultures. Collectively, these data show that tumor-induced suppression mediated by Ia- M phi is caused by increased PGE2 synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)
肿瘤生长通过促使巨噬细胞（Mφ）增加抑制性分子如前列腺素E2（PGE2）的合成或降低其上调分子如II类主要组织相容性复合体蛋白Ia的表达，从而增强巨噬细胞的抑制活性。尽管这些肿瘤诱导的变化是相关的，但尚不清楚荷瘤宿主（TBH）的Ia-Mφ是否通过增加其PGE2合成而变得更具抑制性。为了评估PGE2在肿瘤诱导的Ia-Mφ介导的CD4+T细胞同种异体反应抑制中的作用，将未分离的（富含Ia(+)）或Ia(+)耗尽的（Ia-）小鼠正常宿主（NH）或TBH脾巨噬细胞群体添加到混合淋巴细胞反应（MLR）培养物中。NH或TBH的Ia-Mφ比其各自未分离的群体具有更强的抑制作用，并且TBH的Ia-Mφ比NH的对应物更具抑制作用。当用吲哚美辛阻断PGE2产生时，TBH的Ia-Mφ介导的抑制作用比所有其他巨噬细胞群体介导的抑制作用降低得更多。一种PGE2特异性酶联免疫吸附测定显示，含Ia-Mφ的培养物中的PGE2比含完整巨噬细胞的培养物中的多，含TBH的Ia-Mφ的培养物中的PGE2比NH对应物的培养物中的多。因为干扰素-γ（IFN-γ）是一种有效的巨噬细胞激活分子，可调节Ia表达和PGE2产生，所以研究了IFN-γ对肿瘤诱导的Ia-Mφ介导的抑制作用的影响。外源性IFN-γ降低了除NH未分离的巨噬细胞外所有巨噬细胞群体介导的抑制作用。IFN-γ在没有巨噬细胞或有NH未分离的巨噬细胞的情况下抑制同种异体反应。当巨噬细胞在添加到MLR培养物之前用IFN-γ预孵育时，NH或TBH的Ia-以及TBH未分离的巨噬细胞介导的抑制作用也降低。添加IFN-γ并没有通过降低巨噬细胞PGE2产生来阻断Ia-Mφ介导的抑制作用。事实上，添加IFN-γ使MLR培养物中的PGE2产生增加了两倍。然而，IFN-γ部分降低了添加到巨噬细胞耗尽培养物中的外源性PGE2介导的抑制作用。细胞荧光分析显示，IFN-γ增加了NH和TBH的Ia-Mφ群体中Ia+巨噬细胞的百分比。用抗TNF-α抗体阻断TNF-α活性导致IFN-γ抑制所有添加巨噬细胞的培养物中的同种异体反应。总的来说，这些数据表明，Ia-Mφ介导的肿瘤诱导抑制作用是由PGE2合成增加引起的。（摘要截断于400字）
