Brossart P, Zobywalski A, Grünebach F, Behnke L, Stuhler G, Reichardt V L, Kanz L, Brugger W
Department of Hematology, Oncology, and Immunology, University of Tübingen, Germany.
Cancer Res. 2000 Aug 15;60(16):4485-92.
Interleukin (IL)-10 secretion by tumor cells was demonstrated to be one of the mechanisms by which tumor cells can escape immunological recognition and destruction. In dendritic cells (DCs), which are currently used for vaccination therapies for malignant diseases, IL-10 inhibits IL-12 production and induces a state of antigen-specific anergy in CD4- and CD8-positive T cells. We therefore analyzed the effects of different activation stimuli including lipopolysaccharide (LPS), tumor necrosis factor (TNF)-alpha, and CD40 ligation on IL-10 mediated inhibition of DC development and stimulatory capacity. In our study, the addition of IL-10 to the cultures containing granulocyte/macrophage-colony stimulating factor and IL-4 with or without LPS completely inhibited the generation of DCs from peripheral blood monocytes. These cells remained CD14 positive and expressed high levels of IL-10 receptor (IL-10R), suggesting that IL-10 mediates its effects by up-regulating the IL-10R. In contrast, the simultaneous incubation of monocytes with IL-10 and TNF-alpha or soluble CD40 ligand (sCD40L) resulted in the generation of CD83-positive DCs, induction of nuclear localized RelB, and inhibition of IL-10R up-regulation. DCs grown in the presence of IL-10 and TNF-alpha or sCD40L elicited efficient CTL responses against viral and tumor-associated peptide antigens, which, however, were reduced as compared with DC cultures generated without IL-10. IL-10 decreased the production of IL-6 and the expression of IL-12 in the presence of TNF-alpha or sCD40L, but it had no effect on IL-15, IL-18, and TNF-alpha secretion. Our results show that TNF-alpha or CD40 ligation can antagonize the IL-10-mediated inhibition on DC function, suggesting that depending on activation stimuli, the presence of IL-10 does not necessarily result in T-cell anergy.
肿瘤细胞分泌白细胞介素（IL）-10被证明是肿瘤细胞逃避免疫识别和破坏的机制之一。在目前用于恶性疾病疫苗治疗的树突状细胞（DC）中，IL-10抑制IL-12的产生，并在CD4和CD8阳性T细胞中诱导抗原特异性无反应状态。因此，我们分析了包括脂多糖（LPS）、肿瘤坏死因子（TNF）-α和CD40连接在内的不同激活刺激对IL-10介导的DC发育抑制和刺激能力的影响。在我们的研究中，向含有粒细胞/巨噬细胞集落刺激因子和IL-4的培养物中添加IL-10，无论有无LPS，均完全抑制外周血单核细胞产生DC。这些细胞保持CD14阳性，并高水平表达IL-10受体（IL-10R），表明IL-10通过上调IL-10R来介导其作用。相反，单核细胞与IL-10和TNF-α或可溶性CD40配体（sCD40L）同时孵育会导致产生CD83阳性DC，诱导核定位的RelB，并抑制IL-10R上调。在IL-10和TNF-α或sCD40L存在下生长的DC引发了针对病毒和肿瘤相关肽抗原的有效CTL反应，然而，与没有IL-10产生的DC培养物相比，这种反应有所降低。在TNF-α或sCD40L存在下，IL-10减少了IL-6的产生和IL-12的表达，但对IL-15、IL-18和TNF-α的分泌没有影响。我们的结果表明，TNF-α或CD40连接可以拮抗IL-10介导的对DC功能的抑制，这表明根据激活刺激的不同，IL-10的存在不一定会导致T细胞无反应。
