Regamey Nicolas, Obregon Carolina, Ferrari-Lacraz Sylvie, van Leer Coretta, Chanson Marc, Nicod Laurent P, Geiser Thomas
Division of Respiratory Medicine, University Hospital of Berne, Freiburgstrasse 15, CH-3010 Berne, Switzerland.
Am J Respir Cell Mol Biol. 2007 Jul;37(1):75-84. doi: 10.1165/rcmb.2006-0235OC. Epub 2007 Mar 15.
IL-15 has recently been shown to induce the differentiation of functional dendritic cells (DCs) from human peripheral blood monocytes. Since DCs lay in close proximity to epithelial cells in the airway mucosa, we investigated whether airway epithelial cells release IL-15 in response to inflammatory stimuli and thereby induce differentiation and maturation of DCs. Alveolar (A549) and bronchial (BEAS-2B) epithelial cells produced IL-15 spontaneously and in a time- and dose-dependent manner after stimulation with IL-1beta, IFN-gamma, or TNF-alpha. Airway epithelial cell supernatants induced an increase of IL-15Ralpha gene expression in ex vivo monocytes, and stimulated DCs enhanced their IL-15Ralpha gene expression up to 300-fold. Airway epithelial cell-conditioned media induced the differentiation of ex vivo monocytes into partially mature DCs (HLA-DR+, DC-SIGN+, CD14+, CD80-, CD83+, CD86+, CCR3+, CCR6(+), CCR7-). Based on their phenotypic (CD123+, BDCA2+, BDCA4+, BDCA1(-), CD1a-) and functional properties (limited maturation upon stimulation with LPS and limited capacity to induce T cell proliferation), these DCs resembled plasmacytoid DCs. The effects of airway epithelial cell supernatants were largely blocked by a neutralizing monoclonal antibody to IL-15. Thus, our results demonstrate that airway epithelial cell-conditioned media have the capacity to differentiate monocytes into functional DCs, a process substantially mediated by epithelial-derived IL-15.
最近有研究表明,白细胞介素-15(IL-15)可诱导人外周血单核细胞分化为功能性树突状细胞(DCs)。由于DCs与气道黏膜中的上皮细胞紧密相邻,我们研究了气道上皮细胞是否会在炎症刺激下释放IL-15,从而诱导DCs的分化和成熟。肺泡上皮细胞(A549)和支气管上皮细胞(BEAS-2B)在受到IL-1β、干扰素-γ(IFN-γ)或肿瘤坏死因子-α(TNF-α)刺激后,会自发且呈时间和剂量依赖性地产生IL-15。气道上皮细胞的上清液可使体外培养的单核细胞中IL-15Rα基因表达增加,并且刺激后的DCs其IL-15Rα基因表达增强达300倍。气道上皮细胞条件培养基可诱导体外培养的单核细胞分化为部分成熟的DCs(人类白细胞抗原-DR(HLA-DR)阳性、树突状细胞特异性细胞间黏附分子-3抓取非整合素(DC-SIGN)阳性、CD14阳性、CD80阴性、CD83阳性、CD86阳性、CC趋化因子受体3(CCR3)阳性、CC趋化因子受体6(CCR6)阳性、CC趋化因子受体7(CCR7)阴性)。基于其表型(CD123阳性、血树突状细胞抗原2(BDCA2)阳性、血树突状细胞抗原4(BDCA4)阳性、血树突状细胞抗原1(BDCA1)阴性、CD1a阴性)和功能特性(脂多糖刺激后成熟受限以及诱导T细胞增殖的能力有限),这些DCs类似于浆细胞样DCs。气道上皮细胞上清液的作用在很大程度上被抗IL-15的中和单克隆抗体所阻断。因此,我们的结果表明,气道上皮细胞条件培养基有能力将单核细胞分化为功能性DCs,这一过程主要由上皮来源的IL-15介导。