Shen Weiping, Ladisch Stephan
Center for Cancer Research, Children's National Medical Center, 111 Michigan Avenue, N.W., Washington, DC 20010, USA.
Cell Immunol. 2002 Dec;220(2):125-33. doi: 10.1016/s0008-8749(03)00004-2.
Immunosuppressive membrane gangliosides are released by tumor cells and inhibit normal antigen presenting cell (APC) function. To better understand this process, we have studied the effect of gangliosides on lipopolysaccharide (LPS)-induced maturation of human dendritic cells (DCs). Immature DCs were generated in vitro from human peripheral blood monocytes and were exposed for 72 h to a highly purified ganglioside, G(D1a). During the last 24 h, LPS was added to effect maturation. As assessed by fluorescence activated cell sorting (FACS) analysis, incubation in 50 microM G(D1a) significantly blunted the LPS-induced maturation of the dendritic cells. The expected up-regulation of expression of the co-stimulatory molecules CD80 and CD86 was ablated and that of CD40 was reduced, as were surface CD83 expression and intracellular CD208 production. In addition, ganglioside pretreatment of DC markedly inhibited the allostimulatory capacity and partially prevented the down-regulation of FITC-dextran uptake characteristic of LPS-activated DC. Furthermore, ganglioside-exposed DC also evidenced a broad down-regulation of the cytokine release that is normally initiated by LPS exposure, i.e., there was no increase in IL-1 beta, IL-6, IL-10, IL-12, or tumor necrosis factor (TNF)-alpha release. That a common mechanism may underlie these defects was suggested by the finding that G(D1a) exposure of DC also inhibited the nuclear binding of NF-kappa B that is normally induced by LPS. These results suggest that tumor gangliosides may blunt the anti-tumor immune response in vivo by binding and interfering with dendritic cell maturation.
免疫抑制性膜神经节苷脂由肿瘤细胞释放，可抑制正常抗原呈递细胞（APC）的功能。为了更好地理解这一过程，我们研究了神经节苷脂对脂多糖（LPS）诱导的人树突状细胞（DC）成熟的影响。未成熟的DC由人外周血单核细胞在体外生成，并暴露于高度纯化的神经节苷脂G（D1a）72小时。在最后24小时，加入LPS以促进成熟。通过荧光激活细胞分选（FACS）分析评估，在50μM G（D1a）中孵育显著抑制了LPS诱导的树突状细胞成熟。共刺激分子CD80和CD86表达的预期上调被消除，CD40的表达降低，表面CD83表达和细胞内CD208产生也降低。此外，DC的神经节苷脂预处理显著抑制了同种异体刺激能力，并部分阻止了LPS激活的DC特有的FITC-葡聚糖摄取下调。此外，暴露于神经节苷脂的DC还表现出通常由LPS暴露引发的细胞因子释放广泛下调，即IL-1β、IL-6、IL-10、IL-12或肿瘤坏死因子（TNF）-α释放没有增加。DC暴露于G（D1a）也抑制了通常由LPS诱导的NF-κB核结合，这一发现表明这些缺陷可能有共同的机制。这些结果表明，肿瘤神经节苷脂可能通过结合并干扰树突状细胞成熟来削弱体内的抗肿瘤免疫反应。
