TLR-TLR cross talk in human PBMC resulting in synergistic and antagonistic regulation of type-1 and 2 interferons, IL-12 and TNF-α
TLR-TLR cross talk in human PBMC resulting in synergistic and antagonistic regulation of type-1 and 2 interferons, IL-12 and TNF-α
复制标题
DOI：
10.1016/j.intimp.2007.04.006
复制
发表时间：
2007-08-01
影响因子：
5.6
通讯作者：
Alkan, Sefik S.
中科院分区：
文献类型：
--
作者：
Ghosh, Tarun K.;Mickelson, Dan J.;Alkan, Sefik S.
目前，单一TLR激动剂被用于疫苗接种和肿瘤免疫治疗。在这里，我们研究了TLR激动剂的串联组合对细胞因子产生的影响，主要集中在IFN-α、IFN-β、IFN-γ、TNF-α和IL-12上。使用原代人PBMC培养系统，我们发现TLR 2 -9激动剂的串联组合可以是惰性的、相加的、协同的或拮抗的。最令人感兴趣的组合是TLR 2或TLR 4激动剂与TLR 7/8或TLR 8激动剂的组合。TLR 4-TLR 7/8组合协同上调IFN-γ和IL-12，增强IFN-α，并且还适度诱导TNF-α。TLR 2-TLR 7/8与TLR 4-TLR 7/8一样协同上调IFN-γ，但不上调IL-12。TLR 9激动剂CpG 2216产生高IFN-α，但不能单独或串联上调IFN-γ。此外，TLR 9诱导的1型IFN与TLR 7或TLR 8激动剂组合下调。当与膜渗透性增强剂DOTAP复合使用时，TLR 3诱导显著的IFN-α/-β应答，并且与TLR 2、5、7/8和8的激动剂相加增强应答。据我们所知，这项研究是第一个比较TLR激动剂在人PBMC中的所有可能的串联组合的细胞因子应答。我们鉴定了TLR激动剂的某些组合，其可能具有或可能不具有优于单一激动剂的优点，用于产生在对抗疾病中优选的“最佳细胞因子组合”。(C)2007 Elsevier B. V.保留所有权利。
Currently, single TLR agonists are being utilized for vaccination and tumor immunotherapy. Here we investigated the effects of tandem combinations of TLR agonists on the production of cytokines with major focus on IFN-alpha, -beta, -gamma, TNF-alpha, and IL-12. Using a primary human PBMC culture system, we found that tandem combinations of TLR2-9 agonists can be inert, additive, synergistic or antagonistic. The most interesting combination was TLR2 or TLR4 agonists in combination with TLR7/8 or TLR8 agonists. TLR4-TLR7/8 combinations synergistically up-regulated IFN-gamma and IL-12, enhanced IFN-a and also moderately induced TNF-a. TLR2-TLR7/8 like TLR4-TLR7/8 synergistically up-regulated IFN-gamma but not IL-12. TLR9 agonist CpG2216 produced high IFN-alpha but failed to up regulate IFN-gamma singly or in tandem. Furthermore, TLR9-induced type-1 IFN was down regulated in combination with TLR7, or TLR8 agonists. TLR3 induced significant IFN-alpha/-beta responses when used in a complex with membrane permeability enhancer DOTAP, and additively enhanced response with agonists to TLR2, 5, 7/8, and 8. To our knowledge, this study is the first to compare cytokine responses of all the possible tandem combinations of TLR agonists in human PBMC. We identified certain combinations of TLR agonists that may or may not have advantages over single agonists, for generating an "optimal cytokine combination" preferred in combating diseases. (C) 2007 Elsevier B.V. All rights reserved.