Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7

摘要: Certain C8-substituted and N7, C8-disubstituted guanine ribonucleosides comprise a class of small molecules with immunostimulatory activity. In variety animal models, these agents stimulate both humoral cellular immune responses. The antiviral actions guanosine analogs have been attributed to their ability induce type I IFNs. However, the molecular mechanisms by which potentiate responses are not known. Here, we report that several activate Toll-like receptor 7 (TLR7). 7-Thia-8-oxoguanosine, 7-deazaguanosine, related activated mouse cells in manner analogous known TLR ligands, inducing cytokine production splenocytes (IL-6 IL-12, II IFNs), bone marrow-derived macrophages IL-12), human peripheral blood leukocytes (type IFNs, tumor necrosis factor alpha IL-12). congeners also up-regulated costimulatory MHC I/II dendritic cells. Genetic complementation studies embryonic kidney 293 confirmed exclusively via TLR7. stimulation TLR7 appears require endosomal maturation because inhibition this process chloroquine significantly reduced downstream activation NF-kappaB. TLR8 R-848 TLR2 [S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-R-Cys-S-Ser-Lys4-OH, trihydrochloride)] were inhibited chloroquine, whereas TLR9 CpG oligodeoxynucleotides was abolished. summary, present evidence pathway requires maturation. Thus, B cell-stimulating activities may be explained TLR7-activating capacity.