Division of Innate Immunity, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan.
Section of Oral and Maxillofacial Oncology, Division of Maxillofacial Diagnostic and Surgical Sciences, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
Int Immunol. 2019 Mar 5;31(3):167-173. doi: 10.1093/intimm/dxy075.
Toll-like receptor 8 (TLR8), a sensor for pathogen-derived single-stranded RNA (ssRNA), binds to uridine (Uri) and ssRNA to induce defense responses. We here show that cytidine (Cyd) with ssRNA also activated TLR8 in peripheral blood leukocytes (PBLs) and a myeloid cell line U937, but not in an embryonic kidney cell line 293T. Cyd deaminase (CDA), an enzyme highly expressed in leukocytes, deaminates Cyd to Uri. CDA expression enabled TLR8 response to Cyd and ssRNA in 293T cells. CDA deficiency and a CDA inhibitor both reduced TLR8 responses to Cyd and ssRNA in U937. The CDA inhibitor also reduced PBL response to Cyd and ssRNA. A Cyd analogue, azacytidine, is used for the therapy of myelodysplastic syndrome and acute myeloid leukemia. Azacytidine with ssRNA induced tumor necrosis factor-α expression in U937 and PBLs in a manner dependent on CDA and TLR8. These results suggest that CDA enables TLR8 activation by Cyd or its analogues with ssRNA through deaminating activity. Nucleoside metabolism might impact TLR8 responses in a variety of situations such as the treatment with nucleoside analogues.
Toll 样受体 8（TLR8）是一种识别病原体来源的单链 RNA（ssRNA）的传感器，它可以与尿嘧啶（Uri）和 ssRNA 结合，从而诱导防御反应。我们在此表明，胞嘧啶（Cyd）与 ssRNA 也可以激活外周血白细胞（PBL）和髓样细胞系 U937 中的 TLR8，但不能激活胚胎肾细胞系 293T。胞嘧啶脱氨酶（CDA）是一种在白细胞中高度表达的酶，可将 Cyd 脱氨为 Uri。CDA 表达使 TLR8 能够对 293T 细胞中的 Cyd 和 ssRNA 产生反应。CDA 缺乏和 CDA 抑制剂均可降低 U937 中 TLR8 对 Cyd 和 ssRNA 的反应。Cyd 的类似物阿扎胞苷用于治疗骨髓增生异常综合征和急性髓系白血病。阿扎胞苷与 ssRNA 一起诱导 U937 和 PBL 中肿瘤坏死因子-α的表达，这种方式依赖于 CDA 和 TLR8。这些结果表明，CDA 通过脱氨活性使 TLR8 能够对 Cyd 或其 ssRNA 类似物产生激活作用。核苷代谢可能会影响各种情况下的 TLR8 反应，例如使用核苷类似物进行治疗。
