Nakano Yoshiteru, Kuroda Etsushi, Kito Tomohiro, Yokota Akira, Yamashita Uki
Department of Neurosurgery, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
J Neurosurg. 2006 Apr;104(4):574-82. doi: 10.3171/jns.2006.104.4.574.
It has been reported that glioma cells produce prostaglandin (PG)E2, which promotes the growth of tumor cells and possesses immunosuppressive activity, and that cyclooxygenase (COX) inhibitors impede tumor growth and infiltration. Macrophages in tumor-bearing hosts are activated to produce PGE2, which induces an immunosuppressive state. Note, however, that the precise mechanism by which PGE2 induces an immunosuppressive state is still unclear. In this study, the authors investigated the mechanism of PGE2 production in glioma-bearing hosts.
The human and murine glioma cells that were studied did not produce a significant amount of PGE2. However, the coculture of human peripheral blood mononuclear cells or murine peritoneal macrophages with glioma cells or conditioned glioma medium led to the production of a large amount of PGE2. In contrast, production of tumor necrosis factor and interleukin (IL)-12p70 by macrophages and cytotoxic T lymphocyte induction were suppressed by culturing with conditioned glioma medium; this suppression was abrogated by the addition of the COX inhibitor indomethacin. The macrophagic expression of COX-2, and particularly the expression of microsomal PGE synthase (mPGES)-1, a terminal enzyme of the arachidonate cascade, was enhanced by the glioma-derived soluble factors. Furthermore, IL-12p70 production was not clearly suppressed in macrophages from mPGES-1-deficient mice. The glioma-derived soluble factors were sensitive to treatment with heat and papain.
These results indicated that PGE2 production by macrophages is enhanced by glioma-derived soluble factors, which induce an immunosuppressive state in glioma-bearing hosts. Therefore, the inhibition of PGE2 synthesis, targeting COX-2 and mPGES-1, is an effective treatment for the induction of antiglioma immune responses.
据报道，胶质瘤细胞可产生前列腺素（PG）E2，其可促进肿瘤细胞生长并具有免疫抑制活性，且环氧合酶（COX）抑制剂可阻碍肿瘤生长和浸润。荷瘤宿主中的巨噬细胞被激活以产生PGE2，从而诱导免疫抑制状态。然而，请注意，PGE2诱导免疫抑制状态的确切机制仍不清楚。在本研究中，作者研究了荷胶质瘤宿主中PGE2产生的机制。
所研究的人源和鼠源胶质瘤细胞不会产生大量PGE2。然而，人外周血单核细胞或鼠腹膜巨噬细胞与胶质瘤细胞或胶质瘤条件培养基共培养会导致大量PGE2的产生。相反，巨噬细胞产生肿瘤坏死因子和白细胞介素（IL）-12p70以及细胞毒性T淋巴细胞诱导作用会被胶质瘤条件培养基培养所抑制；添加COX抑制剂吲哚美辛可消除这种抑制作用。胶质瘤衍生的可溶性因子可增强COX-2的巨噬细胞表达，尤其是花生四烯酸级联反应的末端酶微粒体PGE合酶（mPGES）-1的表达。此外，mPGES-1缺陷小鼠的巨噬细胞中IL-12p70的产生并未受到明显抑制。胶质瘤衍生的可溶性因子对热和木瓜蛋白酶处理敏感。
这些结果表明，胶质瘤衍生的可溶性因子可增强巨噬细胞产生PGE2，从而在荷胶质瘤宿主中诱导免疫抑制状态。因此，靶向COX-2和mPGES-1抑制PGE2合成是诱导抗胶质瘤免疫反应的有效治疗方法。
