Wang Leyi, Yang Hongling, Sun Yuan, Yu Fu-Shin X, Wu Xinyi
Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China.
Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, Shandong, PR China
Innate Immun. 2014 Aug;20(6):563-73. doi: 10.1177/1753425913502098. Epub 2013 Sep 17.
TLRs, particularly TLR2 and TLR4, play primary roles in inflammatory responses triggered by Aspergillus fumigatus and lead to the activation of signaling pathways that initiate host defense responses. We previously demonstrated that LPS, a ligand of TLR4, can induce tolerance of A. fumigatus hyphae in telomerase-immortalized human stroma fibroblasts (THSFs). In the present study we investigated the role of TLR4, TLR2 and their downstream signaling pathways in this activity. The THSFs were pretreated with low-dose LPS and then exposed to A. fumigatus hyphae. It was demonstrated that enhanced expression of TLR4, but not of TLR2, was associated with LPS pretreatment. Inhibition of TLR4 with monoclonal Ab prevented reduction of pro-inflammatory cytokine secretion in LPS-pretreated THSFs. Pretreatment of THSFs with low-dose LPS caused an impaired response of the MyD88-dependent classical and MAPK signaling pathway upon subsequent A. fumigatus challenge, while expression of signaling molecules in the MyD88-independent Toll-IL-1 receptor domain-containing adaptor inducing IFN-β pathway was increased in THSFs pretreated with LPS. These results indicated that TLR4 mediates attenuated cytokine production induced by LPS pretreatment, and regulation of MyD88-dependent and MyD88-independent pathways may contribute to the development of A. fumigatus hyphae tolerance in LPS-pretreated THSFs.
Toll样受体（TLRs），尤其是TLR2和TLR4，在烟曲霉引发的炎症反应中起主要作用，并导致启动宿主防御反应的信号通路激活。我们之前证明，TLR4的配体脂多糖（LPS）可诱导端粒酶永生化的人基质成纤维细胞（THSFs）对烟曲霉菌丝产生耐受性。在本研究中，我们调查了TLR4、TLR2及其下游信号通路在该活性中的作用。将THSFs用低剂量LPS预处理，然后暴露于烟曲霉菌丝。结果表明，LPS预处理与TLR4而非TLR2的表达增强有关。用单克隆抗体抑制TLR4可防止LPS预处理的THSFs中促炎细胞因子分泌减少。用低剂量LPS预处理THSFs会导致其在随后受到烟曲霉攻击时，MyD88依赖的经典信号通路和丝裂原活化蛋白激酶（MAPK）信号通路的反应受损，而在用LPS预处理的THSFs中，MyD88非依赖的含Toll-白细胞介素-1受体结构域衔接蛋白诱导干扰素-β（IFN-β）信号通路中的信号分子表达增加。这些结果表明，TLR4介导LPS预处理诱导的细胞因子产生减弱，MyD88依赖和MyD88非依赖信号通路的调节可能有助于LPS预处理的THSFs对烟曲霉菌丝产生耐受性。
