Myers M J, Hanafin W P, Schook L B
Department of Animal Sciences, University of Illinois, Urbana 61801.
Immunopharmacology. 1989 Sep-Oct;18(2):115-24. doi: 10.1016/0162-3109(89)90064-7.
Previous efforts from our laboratory have investigated the mechanisms responsible for dimethylnitrosamine (DMN)-induced suppression of T cell responses. These studies suggested that such changes in T cell activity were most likely to be due to alterations in the down-regulatory signals controlling T cell activation. Accordingly, the production of PGE2, a potent inhibitor of T cell activation, was examined in macrophages obtained from animals exposed to either DMN or vehicle in vivo. The production of PGE2 was determined in macrophages representing various stages of activation (responsive, primed and fully activated) and various stages of differentiation (CSF-1-derived or GM-CSF-derived macrophages). All peritoneal macrophages obtained from DMN-exposed animals demonstrated enhanced production of PGE2 following stimulation with either endotoxin or IFN-gamma as compared to macrophages obtained from vehicle-exposed macrophages. Moreover, the enhanced levels of PGE2 were due to increased PGE2 production rather than to shifts in the kinetics of PGE2 production and utilization. CSF-1- and GM-CSF-induced bone-marrow-derived macrophages (BMDM) produced minimal levels of PGE2, regardless of the in vitro stimulation of cells obtained from either vehicle or DMN treatment groups. Spleen cells obtained from DMN-exposed animals produced significantly higher amounts of PGE2 following endotoxin stimulation compared to control splenocytes. Splenocytes from DMN-exposed animals also demonstrated a suppressed proliferative response to the mitogen Con A. However, when splenocytes from DMN-exposed animals were co-cultured with indomethacin they demonstrated Con A-stimulated proliferative responses similar to the responses of vehicle control splenocytes. These results demonstrate that DMN exposure results in increased PGE2 production by macrophages and that this increase in PGE2 production may be responsible for suppressed T cell responses observed in DMN-exposed animals.
我们实验室之前的研究致力于探究二甲基亚硝胺（DMN）诱导T细胞反应受抑制的机制。这些研究表明，T细胞活性的此类变化很可能是由于控制T细胞激活的下调信号发生了改变。因此，我们检测了从体内暴露于DMN或赋形剂的动物体内获取的巨噬细胞中前列腺素E2（PGE2，一种强效T细胞激活抑制剂）的产生情况。我们测定了代表激活不同阶段（反应性、致敏和完全激活）以及分化不同阶段（CSF-1衍生或GM-CSF衍生巨噬细胞）的巨噬细胞中PGE2的产生量。与从暴露于赋形剂的动物体内获取的巨噬细胞相比，从暴露于DMN的动物体内获取的所有腹膜巨噬细胞在用内毒素或干扰素-γ刺激后均表现出PGE2产生量增加。此外，PGE2水平的升高是由于PGE2产生量增加，而非PGE2产生和利用动力学的改变。无论体外刺激来自赋形剂处理组还是DMN处理组的细胞，CSF-1和GM-CSF诱导的骨髓来源巨噬细胞（BMDM）产生的PGE2水平都极低。与对照脾细胞相比，从暴露于DMN的动物体内获取的脾细胞在内毒素刺激后产生的PGE2量显著更高。从暴露于DMN的动物体内获取的脾细胞对促有丝分裂原刀豆蛋白A的增殖反应也受到抑制。然而，当将从暴露于DMN的动物体内获取的脾细胞与吲哚美辛共同培养时，它们表现出与赋形剂对照脾细胞相似的刀豆蛋白A刺激的增殖反应。这些结果表明，暴露于DMN会导致巨噬细胞产生的PGE2增加，而这种PGE2产生量的增加可能是暴露于DMN的动物体内观察到的T细胞反应受抑制的原因。
