Synergistic effect of Nod1 and Nod2 Agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells
Synergistic effect of Nod1 and Nod2 Agonists with toll-like receptor agonists on human dendritic cells to generate interleukin-12 and T helper type 1 cells
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DOI：
10.1128/iai.73.12.7967-7976.2005
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发表时间：
2005-12-01
影响因子：
3.1
通讯作者：
Takada, H
中科院分区：
文献类型：
--
作者：
Tada, H;Aiba, S;Takada, H
一种合成的 Nod2 激动剂胞壁酰二肽 (MDP) 和两种 Nod1 激动剂 FK565 和 FK156 模仿细菌肽聚糖部分，是诱导细胞介导的免疫（尤其是迟发型超敏反应）的强大佐剂。在这项研究中，我们使用人树突状细胞 (DC) 培养物来检查 MDP 和 FK565/156 与各种合成 Toll 样受体 (TLR) 激动剂（包括合成脂质 A（TLR4 激动剂）、合成三酰基脂肽 Pam3CSSNA（TLR2 激动剂））联合诱导的可能的 1 型 T 辅助细胞 (Th1) 反应， Poly(I:C)（TLR3 激动剂）和 CpG DNA（TLR9 激动剂）。源自人单核细胞的未成熟 DC 表达 Nod1、Nod2、TLR2、TLR3、TLR4 和 TLR9 的 mRNA。用 MDP 和 FK565 与脂质 A、poly(I:C) 和 CpG DNA（但不与 Pam3CSSNA）组合刺激 DC，在培养物上清液中协同诱导白细胞介素 12 (IL-12) p70 和 γ 干扰素 (IFN-gamma)，但不诱导 IL-18，并诱导细胞表面的 IL-15。与细胞因子诱导相关，观察到这些细胞因子基因的 mRNA 表达上调。值得注意的是，与单独使用每种刺激剂刺激相比，用脂质 A 加 MDP 或 FK565 刺激后，IL-12 p35 mRNA 表达增加 >1,000 倍。相反，对于CD83和共刺激分子（例如CD40、CD80和CD86）的表达，在用Nod加TLR激动剂刺激时没有观察到协同效应。用脂质 A 加 MDP 或 FK565 刺激的 DC 培养物上清液激活人 T 细胞，产生高水平的 IFN-γ，并且该活性归因于 DC 衍生的 IL-12。这些发现表明，Nod1 和 Nod2 激动剂与 TLR3、TLR4 和 TLR9 激动剂组合可协同诱导 DC 中 IL-12 和 IFN-γ 的产生，从而诱导 Th1 谱系免疫反应。
A synthetic Nod2 agonist, muramyldipeptide (MDP), and two Nod1 agonists, FK565 and FK156, mimic the bacterial peptidoglycan moiety and are powerful adjuvants that induce cell-mediated immunity, especially delayed-type hypersensitivity. In this study, we used human dendritic cell (DC) cultures to examine possible T helper type 1 (Th1) responses induced by MDP and FK565/156 in combination with various synthetic Toll-like receptor (TLR) agonists, including synthetic lipid A (TLR4 agonist), the synthetic triacyl lipopeptide Pam3CSSNA (TLR2 agonist), poly(I:C) (TLR3 agonist), and CpG DNA (TLR9 agonist). Immature DCs derived from human monocytes expressed mRNAs for Nod1, Nod2, TLR2, TLR3, TLR4, and TLR9. The stimulation of DCs with MDP and FK565 in combination with lipid A, poly(I:C), and CpG DNA, but not with Pam3CSSNA, synergistically induced interleukin-12 (IL-12) p70 and gamma interferon (IFN-gamma), but not IL-18, in culture supernatants and induced IL-15 on the cell surface. In correlation with the cytokine induction, an upregulation of the mRNA expression of these cytokine genes was observed. Notably, IL-12 p35 mRNA expression increased >1,000-fold upon stimulation with lipid A plus either MDP or FK565 compared with stimulation with each stimulant alone. In contrast, for the expression of CD83 and costimulatory molecules such as CD40, CD80, and CD86, no synergistic effects were observed upon stimulation with Nod plus TLR agonists. The culture supernatants of DCs stimulated with lipid A plus either MDP or FK565 activated human T cells to produce high levels of IFN-gamma, and the activity was attributable to DC-derived IL-12. These findings suggest that Nod1 and Nod2 agonists in combination with TLR3, TLR4, and TLR9 agonists synergistically induce IL-12 and IFN-gamma production in DCs to induce Th1-lineage immune responses.