The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduce expression of the inducible nitric oxide synthase gene.
The altered tumoricidal capacity of macrophages isolated from tumor-bearing mice is related to reduce expression of the inducible nitric oxide synthase gene.
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DOI：
10.1084/jem.183.4.1323
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发表时间：
1996-04-01
期刊：
影响因子：
--
通讯作者：
Lopez DM
中科院分区：
文献类型：
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作者：
Dinapoli MR;Calderon CL;Lopez DM
一氧化氮（NO）是活化的巨噬细胞破坏肿瘤细胞的主要效应分子。然而，在许多情况下，发展中的肿瘤似乎能够损害导致NO产生的复杂过程中的步骤，作为避免免疫破坏的一种手段。在用脂多糖（LPS）活化后，来自携带乳腺肿瘤的小鼠的腹膜引发的巨噬细胞（PEM）由于NO的产生减少而显示出它们裂解肿瘤细胞的能力的改变。相反，当这些相同的细胞用LPS与干扰素γ（IFN-γ）组合刺激时，它们能够产生NO并以正常水平裂解靶。由于肿瘤相关巨噬细胞与发展中的肿瘤细胞密切相关，它们产生NO和裂解肿瘤靶标的能力可能与控制肿瘤生长更相关。这群巨噬细胞表现出更严重的不能产生NO和裂解靶点，并且与PEM不同，即使用LPS和IFN-γ的组合处理也不能上调这些功能。北方和西方的印迹显示，诱导型一氧化氮合酶（iNOS）的mRNA和蛋白质水平与每个巨噬细胞群体产生NO的能力直接相关，这些大分子的水平在肿瘤携带者的巨噬细胞中被充分改变，以解释所描述的减少的NO产生。这些结果表明，抑制巨噬细胞溶细胞活性和iNOS表达的空间梯度存在于乳腺肿瘤荷瘤小鼠中，由此来自肿瘤内的巨噬细胞表现出比更远侧定位的PEM更明显的抑制。这种抑制可能是由于巨噬细胞接近发展中的肿瘤，巨噬细胞成熟状态，或两者兼而有之。
Nitric oxide (NO) is a major effector molecule in the destruction of tumor cells by activated macrophages. However, in many cases, developing neoplasms appear to be capable of impairing steps in the complex process leading to NO production as a means of avoiding immune destruction. After activation with lipopolysaccharide (LPS), peritoneal- elicited macrophages (PEM) from mice bearing mammary tumors display alterations in their ability to lyse tumor cells due to reduced production of NO. In contrast, when these same cells are stimulated with LPS in combination with interferon gamma (IFN-gamma), they are able to produce NO and lyse targets at normal levels. Since tumor- associated macrophages are intimately associated with the cells of the developing tumor, their ability to produce NO and lyse tumor targets is likely to be more relevant to controlling tumor growth. This population of macrophages exhibited a more profound inability to produce NO and lyse targets and, unlike the PEM, was not able to upregulate these functions even when treated with combinations of LPS and IFN-gamma. Northern and Western blots revealed that inducible nitric oxide synthase (iNOS) mRNA and protein levels correlated directly with the ability of each macrophage population to produce NO, and the levels of these macromolecules were altered sufficiently in tumor bearers' macrophages to account for the diminished NO production described. These results indicate that a spatial gradient of suppression of macrophage cytolytic activity and iNOS expression exists in mammary tumor-bearing mice, whereby macrophages from within the tumor exhibit a more pronounced suppression than the more distally located PEM. This suppression may be due to proximity of the macrophages to the developing tumor, macrophage maturational state, or both.