Fu Shu-Ling, Lin Chun-Cheng, Hsu Ming-Ling, Liu Sheng-Hung, Huang Yu-Chuen, Chen Yu-Jen
Institute of Traditional Medicine, National Yang-Ming University, Taipei, Taiwan.
Department of Chemistry, National Tsing Hua University, Hsinchu, Taiwan.
Oncotarget. 2016 Mar 8;7(10):11677-86. doi: 10.18632/oncotarget.7315.
CCL-34, a synthetic α-galactosylceramide analog, has been reported as an activator of toll-like receptor 4 (TLR4) in macrophages. TLR4 is highly expressed in dendritic cell (DC) and several TLR4 agonists are known to trigger DC maturation. We herein evaluated the effect of CCL-34 on DC maturation. Human CD14+ monocyte-derived immature DC were treated with CCL-34, its inactive structural analog CCL-44, or LPS to assess the DC maturation. CCL-34 induced DC maturation according to their characteristically dendrite-forming morphology, CD83 expression and IL-12p70 production. The allostimulatory activity of DC on proliferation of naive CD4+CD45+RA+ T cells and their secretion of interferon-γ was increased by CCL-34. Phagocytosis, an important function of immature DC, was reduced after CCL-34 treatment. All these effects related to DC maturation were evidently induced by positive control LPS but not by CCL-44 treatment. TLR4 neutralization impaired human DC maturation triggered by CCL-34. The induction of IL-12, a hallmark of DC maturation, by CCL-34 and LPS was only evident in TLR4-competent C3H/HeN, but not in TLR4-defective C3H/HeJ mice. CCL-34 could further elicit the antigen presentation capability in mice inoculated with doxorubicin-treated colorectal cancer cells. In summary, CCL-34 triggers DC maturation via a TLR4-dependent manner, which supports its potential application as an immunostimulator.
CCL-34是一种合成的α-半乳糖神经酰胺类似物，据报道它是巨噬细胞中Toll样受体4（TLR4）的激活剂。TLR4在树突状细胞（DC）中高度表达，已知几种TLR4激动剂可触发DC成熟。我们在此评估了CCL-34对DC成熟的影响。用CCL-34、其无活性结构类似物CCL-44或LPS处理人CD14+单核细胞衍生的未成熟DC，以评估DC成熟情况。CCL-34根据其特征性的树突形成形态、CD83表达和IL-12p70产生诱导DC成熟。CCL-34增强了DC对幼稚CD4+CD45+RA+T细胞增殖的共刺激活性及其干扰素-γ的分泌。吞噬作用是未成熟DC的一项重要功能，CCL-34处理后吞噬作用降低。所有这些与DC成熟相关的效应均由阳性对照LPS明显诱导，而CCL-44处理则无此作用。TLR4中和可损害CCL-34触发的人DC成熟。CCL-34和LPS诱导的IL-12（DC成熟的标志）仅在具有TLR4功能的C3H/HeN小鼠中明显，而在缺乏TLR4的C3H/HeJ小鼠中则不明显。CCL-34可进一步提高接种阿霉素处理的结肠癌细胞的小鼠的抗原呈递能力。总之，CCL-34通过依赖TLR4的方式触发DC成熟，这支持了其作为免疫刺激剂的潜在应用。
