Di Carlo E, Coletti A, Modesti A, Giovarelli M, Forni G, Musiani P
Institute of Human Pathology and Social Medicine, University of Chieti, Italy.
Eur Cytokine Netw. 1998 Mar;9(1):61-8.
Tumor cells engineered to release cytokines are a valuable tool for investigating biological activities elicited by local cytokines. The parental cells of a mouse mammary adenocarcinoma (TSA-pc) were transduced with the cDNA coding for mouse interleukin-10 (IL-10). In vitro, transduced TSA cells secrete about 200 ng of IL-10/10(5) seeded cells in 48 hours (TSA-IL-10). When injected subcutaneously into syngeneic BALB/c mice, TSA-IL-10 cells gave rise to a tumor that grew progressively during the first 7-10 days and then rapidly and completely regressed. To study the events associated with this growth and disappearance, histological, immunohistochemical and ultrastructural analyses of the tumor area were performed at progressive times after challenge. A slow, but progressive and massive recruitment of leukocytes (mainly macrophages and neutrophils) into the tumor was evident. Several CD8+, CD4+ lymphocytes and a few NK cells were present. Marked inhibition of neoangiogenesis was also observed. On day 9, the microvascular network in the growth area had almost vanished, while vascular damage was present in the surrounding stromal tissue. From day 4, down-modulation of VEGF expression in the tumor area and inhibition of tumor necrosis factor-alpha (TNF-alpha) and IL-6 production by reactive leukocytes were evident. The few vessels present in the tumor area displayed poor expression of monocyte chemotactic protein-1 (MCP-1), moderate expression of VCAM-1, and strong expression of ELAM-1, three molecules that result in adhesion of inflammatory cells to the endothelium. A few tumor-infiltrating macrophages were moderately stained with anti-iNOS antibodies. These findings suggest that the collapse of established TSA-IL-10 tumors is the result of the pro- and anti-inflammatory activity of IL-10, which: a) is a signal for the local recruitment of leukocytes; b) leads to vascular damage; c) suppresses cytokine production. The coexistence of both a direct stimulatory activity on endothelial cells and an anti-angiogenic activity is evidence of the ambivalence of the local effects of IL-10.
经过基因工程改造以释放细胞因子的肿瘤细胞是研究局部细胞因子引发的生物学活性的宝贵工具。用编码小鼠白细胞介素-10（IL-10）的cDNA转导小鼠乳腺腺癌的亲本细胞（TSA-pc）。在体外，转导的TSA细胞在48小时内每10⁵接种细胞分泌约200 ng的IL-10（TSA-IL-10）。当皮下注射到同基因BALB/c小鼠中时，TSA-IL-10细胞形成一个肿瘤，该肿瘤在最初的7 - 10天内逐渐生长，然后迅速完全消退。为了研究与这种生长和消失相关的事件，在攻击后的不同时间对肿瘤区域进行了组织学、免疫组织化学和超微结构分析。明显可见白细胞（主要是巨噬细胞和中性粒细胞）缓慢但逐渐大量募集到肿瘤中。存在一些CD8⁺、CD4⁺淋巴细胞和少数NK细胞。还观察到新生血管生成受到明显抑制。在第9天，生长区域的微血管网络几乎消失，而周围基质组织中存在血管损伤。从第4天起，肿瘤区域VEGF表达下调以及反应性白细胞对肿瘤坏死因子-α（TNF-α）和IL-6产生的抑制作用明显。肿瘤区域中存在的少数血管显示单核细胞趋化蛋白-1（MCP-1）表达不佳、血管细胞黏附分子-1（VCAM-1）表达中等以及E选择素（ELAM-1）表达强烈，这三种分子导致炎症细胞黏附于内皮。少数肿瘤浸润巨噬细胞用抗诱导型一氧化氮合酶（iNOS）抗体染色呈中度阳性。这些发现表明，已建立的TSA-IL-10肿瘤的消退是IL-10的促炎和抗炎活性的结果，即：a）是局部募集白细胞的信号；b）导致血管损伤；c）抑制细胞因子产生。IL-10对内皮细胞既有直接刺激活性又有抗血管生成活性，这证明了IL-10局部作用的矛盾性。
