Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists
Synergistic stimulation of human monocytes and dendritic cells by Toll-like receptor 4 and NOD1- and NOD2-activating agonists
复制标题
DOI：
10.1002/eji.200526286
复制
发表时间：
2005-08-01
影响因子：
5.4
通讯作者：
Adib-Conquy, M
中科院分区：
文献类型：
--
作者：
Fritz, JH;Girardin, SE;Adib-Conquy, M
胞肽是细菌肽聚糖（PG）的降解产物，由核苷酸结合寡聚化结构域1（NOD 1）和NOD 2（最近发现的模式识别分子（PRM）家族的成员）感知。其中一种胞壁肽（MDP）通过NOD 2介导细胞信号传导，发挥佐剂活性，并与脂多糖（LPS）协同作用，在体外和体内诱导促炎症反应。相比之下，关于NODI激动剂的刺激能力存在很少且矛盾的结果。因此，检测了NOD 1（MurNAc-L-Ala-gamma-D-Glu-meso-二氨基庚二酸，MtriDAP）和NOD 2（MurNAc-L-Ala-D-isoGln，MDP; MurNAc-L-Ala-gamma-D-Glu-L-Lys，MtriLYS）激动剂活化原代人骨髓细胞的能力。我们发现CD 14（+）单核细胞和CD 1a（+）未成熟树突状细胞（DC）都表达NOD 1和NOD 2 mRNA。用高度纯化的胞肽（MtriDAP、MDP和MtriLYS）刺激原代人单核细胞和DC诱导促炎细胞因子的释放。我们在这里揭示，NOD 1以及NOD 2激动剂与LPS协同作用，以刺激这些骨髓细胞亚群中促炎细胞因子和抗炎细胞因子的释放。最后，我们报告NOD 1以及NOD 2激动剂与亚活性剂量的LPS协同作用以诱导DC成熟，表明NOD激动剂与Toll样受体4感测的分子协同作用以指示适应性免疫应答的发生。
Muropeptides are degradation products of bacterial peptidoglycan (PG) sensed by nucleotide-binding oligomerization domain 1 (NODI) and NOD2, members of a recently discovered family of pattern recognition molecules (PRM). One of these muropeptides, muramyl dipeptide (MDP) mediates cell signaling by NOD2, exerts adjuvant activity and synergizes with lipopolysaccharide (LPS) to induce proinflammatory responses in vitro and in vivo. In contrast, few and contradictory results exist about the stimulatory capacity of NODI agonists. Thus, the ability of NOD1 (MurNAc-L-Ala-gamma-D-Glu-meso-diaminopimelic acid, MtriDAP) and NOD2 (MurNAc-L-Ala-D-isoGIn, MDP; MurNAc-L-Ala-gamma-D-GIu-L-Lys, MtriLYS) agonists to activate primary human myeloid cells was examined. We show that both CD14(+) monocytes and CD1a(+) immature dendritic cells (DC) express NODI and NOD2 mRNA. Stimulation of primary human monocytes and DC with highly purified muropeptides (MtriDAP, MDP and MtriLYS) induces release of pro-inflammatory cytokines. We reveal here that NOD1 as well as NOD2 agonists act cooperatively with LPS to stimulate the release of both pro- and anti-inflammatory cytokines in these myeloid cell subsets. Finally, we report that NOD1 as well as NOD2 agonists synergize with sub-active doses of LPS to induce DC maturation, demonstrating that NOD agonists act cooperatively with molecules sensed by Toll-like receptor 4 to instruct the onset of adaptive immune responses.