Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling
Heterodimerization of TLR2 with TLR1 or TLR6 expands the ligand spectrum but does not lead to differential signaling
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DOI：
10.1189/jlb.0807586
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发表时间：
2008-03-01
影响因子：
5.5
通讯作者：
Ulmer, Artur J.
中科院分区：
文献类型：
--
作者：
Farhat, Katja;Riekenberg, Sabine;Ulmer, Artur J.
TLR是先天免疫系统的主要触发因子，通过保守的病原体相关分子模式识别各种微生物。TLR 2是细菌脂肽（LP）的功能性识别的受体，并且在诸如慢性阻塞性肺疾病和脓毒症的各种病症期间被上调。该受体的独特之处在于其与TLR 1或TLR 6形成异聚体以介导细胞内信号传导的能力。根据脂肪酸模式以及多肽尾部的组装，LP可以以TLR 1或TLR 6依赖性方式通过TLR 2信号传导。还有二酰化和三酰化LP，其刺激TLR 1缺陷细胞和TLR 6缺陷细胞。在这项研究中，我们研究了异源二聚化是否进化发展，以扩大配体谱或诱导不同的免疫反应。我们使用三种LP，棕榈酸（Pam）辛酸（Oct）（2）C-（VPGVG）（4）VPGKG，成纤维细胞刺激LP-1和Pam 2C-SK 4，分析了通过不同TLR 2二聚体激活的信号转导途径。信号分子的显性负性形式、MAPK的免疫印迹以及微阵列分析表明，所有二聚体使用相同的信号级联，导致相同的基因激活模式。我们的结论是，TLR 2与TLR 1或TLR 6的异源二聚化进化发展，以扩大配体谱，使先天免疫系统能够识别各种病原体中存在的许多不同结构的LP。因此，虽然支原体和革兰氏阳性和革兰氏阴性细菌可能会激活不同的TLR 2二聚体，不同的信号通路的发展，以响应不同的LP似乎并没有至关重要的意义的先天防御系统。
TLR are primary triggers of the innate immune system by recognizing various microorganisms through conserved pathogen-associated molecular patterns. TLR2 is the receptor for a functional recognition of bacterial lipopeptides (LP) and is up-regulated during various disorders such as chronic obstructive pulmonary disease and sepsis. This receptor is unique in its ability to form heteromers with TLR1 or TLR6 to mediate intracellular signaling. According to the fatty acid pattern as well as the assembling of the polypeptide tail, LP can signal through TLR2 in a TLR1- or TLR6-dependent manner. There are also di- and triacylated LP, which stimulate TLR1- deficient cells and TLR6-deficient cells. In this study, we investigated whether heterodimerization evolutionarily developed to broaden the ligand spectrum or to induce different immune responses. We analyzed the signal transduction pathways activated through the different TLR2 dimers using the three LP, palmitic acid (Pam) octanoic acid (Oct)(2)C-(VPGVG)(4)VPGKG, fibroblast-stimulating LP-1, and Pam2C-SK4. Dominant-negative forms of signaling molecules, immunoblotting of MAPK, as well as microarray analysis indicate that all dimers use the same signaling cascade, leading to an identical pattern of gene activation. We conclude that heterodimerization of TLR2 with TLR1 or TLR6 evolutionarily developed to expand the ligand spectrum to enable the innate immune system to recognize the numerous, different structures of LP present in various pathogens. Thus, although mycoplasma and Gram-positive and Gram-negative bacteria may activate different TLR2 dimers, the development of different signal pathways in response to different LP does not seem to be of vital significance for the innate defense system.