Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7
Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: Activation of Toll-like receptor 7
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DOI：
10.1073/pnas.0631696100
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发表时间：
2003-05-27
影响因子：
11.1
通讯作者：
Cottam, HB
中科院分区：
文献类型：
--
作者：
Lee, J;Chuang, TH;Cottam, HB
某些C8取代的和N7、C8二取代的鸟嘌呤核糖核苷构成一类具有免疫刺激活性的小分子。在各种动物模型中，这些药剂刺激体液和细胞免疫应答。这些鸟苷类似物的抗病毒作用归因于它们诱导I型IFN的能力。然而，鸟苷类似物增强免疫应答的分子机制尚不清楚。在这里，我们报告，几个鸟苷类似物激活Toll样受体7（TLR 7）。7-硫-8-氧代鸟苷、7-脱氮鸟苷和相关鸟苷类似物以类似于已知TLR配体的方式激活小鼠免疫细胞，诱导小鼠脾细胞（IL-6和IL-12，I型和II型IFN）、骨髓衍生的巨噬细胞（IL-6和IL-12）和人外周血白细胞（I型IFN，肿瘤坏死因子α和IL-12）中的细胞因子产生。鸟苷同源物还上调树突状细胞中的共刺激分子和MHC I/II。在人胚肾293细胞中的遗传互补研究证实，鸟苷类似物仅通过TLR 7激活细胞。人细胞中鸟苷类似物对TLR 7的刺激似乎需要内体成熟，因为用氯喹抑制该过程显著降低了NF-κ B的下游活化。然而，R-848对TLR 8的激活和S-[2，3-双（棕榈酰氧基）-（2-RS）-丙基]-N-棕榈酰-R-Cys-S-Ser-Lys 4-OH，三盐酸盐）对TLR 2的激活不被氯喹抑制，而CpG寡脱氧核苷酸对TLR 9的激活被消除。总之，我们提出的证据表明，鸟苷类似物激活免疫细胞通过TLR 7的途径，需要内体成熟。因此，鸟苷类似物的B细胞刺激和抗病毒活性可以通过它们的TLR 7活化能力来解释。
Certain C8-substituted and N7, C8-disubstituted guanine ribonucleosides comprise a class of small molecules with immunostimulatory activity. In a variety of animal models, these agents stimulate both humoral and cellular immune responses. The antiviral actions of these guanosine analogs have been attributed to their ability to induce type I IFNs. However, the molecular mechanisms by which the guanosine analogs potentiate immune responses are not known. Here, we report that several guanosine analogs activate Toll-like receptor 7 (TLR7). 7-Thia-8-oxoguanosine, 7-deazaguanosine, and related guanosine analogs activated mouse immune cells in a manner analogous to known TLR ligands, inducing cytokine production in mouse splenocytes (IL-6 and IL-12, type I and II IFNs), bone marrow-derived macrophages (IL-6 and IL-12), and in human peripheral blood leukocytes (type I IFNs, tumor necrosis factor a and IL-12). The guanosine congeners also up-regulated costimulatory molecules and MHC I/II in dendritic cells. Genetic complementation studies in human embryonic kidney 293 cells confirmed that the guanosine analogs activate cells exclusively via TLR7. The stimulation of TLR7 by the guanosine analogs in human cells appears to require endosomal maturation because inhibition of this process with chloroquine significantly reduced the downstream activation of NF-kappaB. However, TLR8 activation by R-848 and TLR2 activation by {S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-R-Cys-S-Ser-Lys4-OH, trihydrochloride)) were not inhibited by chloroquine, whereas TLR9 activation by CpG oligodeoxynucleotides was abolished. In summary, we present evidence that guanosine analogs activate immune cells via TLR7 by a pathway that requires endosomal maturation. Thus, the B cell-stimulating and antiviral activities of the guanosine analogs may be explained by their TLR7-activating capacity.