Alleva D G, Burger C J, Elgert K D
Department of Biology, Microbiology, Virginia Polytechnic Institute and State University, Blacksburg 24061-0406.
J Immunol. 1994 Aug 15;153(4):1674-86.
In vitro-activated macrophages (Mphi) co-express cytotoxicity for tumor cells and suppression of lymphocyte proliferation. These Mphi functions increase during tumor growth and are mediated by soluble molecules. Because Mphi-derived nitric oxide (NO) and TNF-alpha mediate both cytotoxicity and suppression, we determined whether fibrosarcoma (Meth-KDE) growth increased Mphi-mediated suppression of T cell proliferation by increasing Mphi NO and TNF-alpha production. Tumor-bearing host peritoneal Mphi produced more NO and TNF-alpha than normal host Mphi when activated with IFN-gamma or LPS, respectively. This tumor-induced increase in Mphi NO and TNF-alpha production mediated suppression of alloantigen-driven T cell proliferation, because treatment with either NG-monomethyl-L-arginine or anti-TNF-alpha Ab blocked tumor-bearing host Mphi-mediated suppression. TNF-alpha did not directly suppress T cells, but it induced Mphi NO production that down-regulated proliferation. When non-tumor-infiltrating peritoneal Mphi were cultured with Meth-KDE cell supernatants, Mphi production of NO and TNF-alpha was strongly down-regulated. The tumor-derived molecules responsible for this inhibition were IL-10, TGF-beta 1, and prostaglandin E2. The experimental evidence leading to this conclusion included: 1) The Meth-KDE cells produced significant levels of these cytokines. 2) Recombinant forms of these cytokines suppressed NO and TNF-alpha production. 3) Ab-mediated absorption of these cytokines from tumor cell supernatants restored NO and TNF-alpha production. 4) Anti-IL-10 and anti-TGF-beta 1 Ab addition to IFN-gamma-stimulated Mphi restored NO production. Culture supernatants of two human carcinoma cell lines and another murine fibrosarcoma suppressed Mphi NO and TNF-alpha production, which was partly mediated by TGF-beta 1 and prostaglandin E2. Collectively, these results suggest that tumor growth promotes distal Mphi suppressor activity by increasing Mphi production of cytotoxic molecules and concomitantly down-regulating the local production of these antitumor molecules.
体外激活的巨噬细胞（Mphi）对肿瘤细胞共表达细胞毒性并抑制淋巴细胞增殖。这些Mphi功能在肿瘤生长过程中增强，并由可溶性分子介导。由于Mphi衍生的一氧化氮（NO）和肿瘤坏死因子-α（TNF-α）介导细胞毒性和抑制作用，我们确定纤维肉瘤（Meth-KDE）的生长是否通过增加Mphi的NO和TNF-α产生来增强Mphi介导的T细胞增殖抑制作用。荷瘤宿主腹膜巨噬细胞在用γ干扰素（IFN-γ）或脂多糖（LPS）激活时，分别比正常宿主巨噬细胞产生更多的NO和TNF-α。这种肿瘤诱导的Mphi的NO和TNF-α产生增加介导了对同种异体抗原驱动的T细胞增殖的抑制，因为用NG-单甲基-L-精氨酸或抗TNF-α抗体处理可阻断荷瘤宿主Mphi介导的抑制作用。TNF-α并不直接抑制T细胞，但它诱导Mphi产生NO从而下调增殖。当非肿瘤浸润性腹膜巨噬细胞与Meth-KDE细胞上清液一起培养时，Mphi的NO和TNF-α产生被强烈下调。负责这种抑制作用的肿瘤衍生分子是白细胞介素-10（IL-10）、转化生长因子-β1（TGF-β1）和前列腺素E2。得出这一结论的实验证据包括：1）Meth-KDE细胞产生了大量这些细胞因子。2）这些细胞因子的重组形式抑制了NO和TNF-α的产生。3）抗体介导的从肿瘤细胞上清液中吸收这些细胞因子可恢复NO和TNF-α的产生。4）向IFN-γ刺激的巨噬细胞中添加抗IL-10和抗TGF-β1抗体可恢复NO的产生。两个人类癌细胞系和另一种小鼠纤维肉瘤的培养上清液抑制了巨噬细胞的NO和TNF-α产生，这部分由TGF-β1和前列腺素E2介导。总体而言，这些结果表明肿瘤生长通过增加巨噬细胞细胞毒性分子的产生并同时下调这些抗肿瘤分子的局部产生来促进远处巨噬细胞的抑制活性。
