The human toll like receptor 9 (TLR9) detects differences between microbial and host DNA, based on unmethylated deoxycytidyl deoxyguanosine dinucleotide (CpG) motifs, leading to activation of both innate and adaptive immune mechanisms. The synthetic TLR9 agonist, CpG-ODN, can substitute for microbial DNA in these responses, and is in clinical trials as an immunomodulatory agent in diseases as diverse as infections, cancer and allergic disorders. Human TLR9 is expressed on cells of haematopoietic origin (principally plasmacytoid dendritic cells and B cells), but has also been described as being expressed on a number of other cell types. In order to clarify the expression and function of TLR9 in a range of cells of both haematopoietic and non-haematopoietic origin, we investigated the level of expression of TLR9 mRNA, and the ability of the cells to respond to CpG-ODN by upregulation of cell surface markers, cytokine production, cellular proliferation and activation of NFkappaB. Our data show that the cellular response to CpG-ODN depended on a threshold level of expression of TLR9. TLR9 was widely expressed amongst B cell tumours (with the exception of myeloma cell lines), but we did not find either threshold levels of expression of TLR9 or responses to CpG-ODN in several myeloma or myeloid tumour cell lines or any non-haematological tumour cell lines tested in our study. TLR9-positive cells varied significantly in their responses to CpG-ODN, and the level of TLR9 expression beyond the threshold did not correlate with the magnitude of the response to CpG-ODN. Finally, CpG-ODN induced NFkappaB activation and increased cellular proliferation in Hek293 cells that had been stably transfected with hTLR9, but did not affect the expression of surface markers or synthesis of IL-6, IL-10 or TNF-alpha. Thus both haematological and non-haematological cells expressing appropriate levels of TLR9 respond to CpG-ODN, but the nature of the TLR9-mediated response is dependent on cell type.

中文翻译：

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TLR9 mRNA的阈值水平可预测血液和非血液肿瘤细胞系对CpG-ODN的细胞反应性。

人类通行费像受体9（TLR9）基于未甲基化的脱氧胞苷基脱氧鸟苷二核苷酸（CpG）基序来检测微生物和宿主DNA之间的差异，从而导致先天免疫机制和适应性免疫机制的激活。合成的TLR9激动剂CpG-ODN可以替代这些反应中的微生物DNA，并且在临床试验中作为免疫调节剂用于多种疾病，如感染，癌症和过敏性疾病。人TLR9在造血起源的细胞（主要是浆细胞样树突状细胞和B细胞）上表达，但也被描述为在许多其他细胞类型上表达。为了阐明TLR9在造血和非造血来源的一系列细胞中的表达和功能，我们研究了TLR9 mRNA的表达水平，以及细胞通过上调细胞表面标志物，细胞因子产生，细胞增殖和激活NFkappB来响应CpG-ODN的能力。我们的数据表明，细胞对CpG-ODN的反应取决于TLR9表达的阈值水平。TLR9在B细胞肿瘤中广泛表达（骨髓瘤细胞系除外），但在几种骨髓瘤或骨髓瘤细胞系或任何非血液系统肿瘤中，我们均未发现TLR9表达的阈值水平或对CpG-ODN的反应在我们的研究中测试的细胞系。TLR9阳性细胞对CpG-ODN的反应差异很大，并且超过阈值的TLR9表达水平与对CpG-ODN的反应强度无关。最后，CpG-ODN在已被hTLR9稳定转染但未影响表面标志物的表达或IL-6，IL-10或TNF-α合成的Hek293细胞中诱导NFkappaB活化并增加细胞增殖。因此，表达适当水平的TLR9的血液和非血液细胞都对CpG-ODN产生反应，但是TLR9介导的反应的性质取决于细胞类型。