血管内皮生长因子抑制脂多糖诱导的树突状细胞成熟，但不抑制促炎细胞因子诱导的树突状细胞成熟。
Vascular endothelial growth factor inhibits maturation of dendritic cells induced by lipopolysaccharide, but not by proinflammatory cytokines.
作者信息
Takahashi Akihiro, Kono Koji, Ichihara Fumiko, Sugai Hidemitsu, Fujii Hideki, Matsumoto Yoshiro
机构信息
First Department of Surgery, University of Yamanashi, 1110 Shimokato, 409-3898 Tamaho, Yamanashi, Japan.
出版信息
Cancer Immunol Immunother. 2004 Jun;53(6):543-50. doi: 10.1007/s00262-003-0466-8. Epub 2003 Dec 10.
PURPOSE
Dendritic cells (DCs) play an important role in the host's immunosurveillance against cancer. It has been shown that the function of DCs is impaired and their population decreased in a cancer-bearing host. In the present study, we investigated the mechanism of down-regulation of DCs in a cancer-bearing host.
METHODS
We evaluated the relationship between DC infiltration and production of vascular endothelial growth factor (VEGF) in carcinoma tissue by immunohistochemistry. Furthermore, functional and phenotypical alterations of DCs were evaluated when monocyte-derived, mature DCs were treated with VEGF in vitro. Monocyte-derived DCs were generated in a culture of monocyte with interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor, and the maturation of DCs was induced by either lipopolysaccharide (LPS) or a proinflammatory cytokine cocktail: tumor-necrosis factor alpha, prostaglandin E2, IL-6, and IL-1beta.
RESULTS
A significant inverse correlation was found between the density of DCs and the quantity of VEGF production in gastric carcinoma tissue (r=-0.39, p<0.05). In LPS-induced maturation, the ability of mature DCs to stimulate allogenic T cells and produce IL-12 (p70 heterodimer) was suppressed by the addition of VEGF in a dose-dependent manner. A lesser expression of costimulatory molecules (CD80 and CD86) was seen in DCs treated with exogenous VEGF than in DCs not treated with VEGF. The population of dead DCs (early and late apoptosis) treated with VEGF increased more than that without VEGF treatment, using the annexin V and propidium iodide evaluation in DCs matured by LPS. In contrast, in DCs matured by the proinflammatory cytokine cocktail, the down-regulation of costimulatory molecules and induction of DC apoptosis was not seen.
CONCLUSIONS
These findings show that the inhibition of DC maturation by VEGF differs depending on the maturation status of the DCs.
目的
树突状细胞（DCs）在宿主对癌症的免疫监视中发挥重要作用。研究表明，在荷癌宿主中DCs的功能受损且其数量减少。在本研究中，我们调查了荷癌宿主中DCs下调的机制。
方法
我们通过免疫组织化学评估了癌组织中DC浸润与血管内皮生长因子（VEGF）产生之间的关系。此外，当体外将单核细胞来源的成熟DCs用VEGF处理时，评估了DCs的功能和表型改变。单核细胞来源的DCs在单核细胞与白细胞介素4（IL-4）和粒细胞-巨噬细胞集落刺激因子的培养物中产生，并且DCs的成熟由脂多糖（LPS）或促炎细胞因子混合物诱导：肿瘤坏死因子α、前列腺素E2、IL-6和IL-1β。
结果
在胃癌组织中发现DCs密度与VEGF产生量之间存在显著负相关（r = -0.39，p < 0.05）。在LPS诱导的成熟过程中，添加VEGF以剂量依赖方式抑制了成熟DCs刺激同种异体T细胞和产生IL-12（p70异二聚体）的能力。与未用VEGF处理的DCs相比，用外源性VEGF处理的DCs中协同刺激分子（CD80和CD86）的表达较低。使用膜联蛋白V和碘化丙啶评估LPS成熟的DCs，用VEGF处理的死亡DCs（早期和晚期凋亡）群体比未用VEGF处理的增加更多。相反，在由促炎细胞因子混合物成熟的DCs中，未观察到协同刺激分子的下调和DC凋亡的诱导。
结论
这些发现表明，VEGF对DC成熟的抑制因DCs的成熟状态而异。
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