Induction of macrophagic prostaglandin E2 synthesis by glioma cells.
Induction of macrophagic prostaglandin E2 synthesis by glioma cells.
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DOI：
10.3171/jns.2006.104.4.574
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发表时间：
2006-04
影响因子：
4.1
通讯作者：
Yoshiteru Nakano;E. Kuroda;Tomohiro Kito;A. Yokota;U. Yamashita
中科院分区：
文献类型：
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作者：
Yoshiteru Nakano;E. Kuroda;Tomohiro Kito;A. Yokota;U. Yamashita
目的胶质瘤细胞产生前列腺素(PG)E2，促进肿瘤细胞生长并具有免疫抑制活性，而环氧合酶(COX)抑制剂可抑制肿瘤生长和侵袭。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。在这项研究中，作者研究了PGE2在胶质瘤宿主中产生的机制。方法所研究的人和小鼠胶质瘤细胞不产生明显的PGE2。然而，人外周血单个核细胞或小鼠腹膜巨噬细胞与胶质瘤细胞或胶质瘤条件培养液共培养时，会产生大量的PGE2。相反，巨噬细胞产生肿瘤坏死因子和白介素12p70以及细胞毒性T淋巴细胞的诱导被胶质瘤条件培养液培养所抑制；这种抑制作用可被COX抑制剂消炎痛所取消。胶质瘤来源的可溶性因子可促进巨噬细胞COX-2的表达，尤其是花生四烯酸级联反应的末端酶微粒体前列腺素E合成酶(MPGES)-1的表达。此外，mPGES-1缺陷小鼠的巨噬细胞中IL-12p70的产生没有受到明显的抑制。胶质瘤来源的可溶性因子对热和木瓜酶处理敏感。结论胶质瘤来源的可溶性因子可促进巨噬细胞产生PGE2，使荷瘤宿主处于免疫抑制状态。因此，以COX-2和mPGES-1为靶点抑制PGE2的合成是诱导抗胶质瘤免疫反应的有效治疗方法。
OBJECT 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. METHODS 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. CONCLUSIONS 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.