Oligodeoxynucleotides differentially modulate activation of TLR7 and TLR8 by imidazoquinolines.
Among the 11 human TLRs, a subfamily TLR7, TLR8, and TLR9 display similarities in structure and endosomal localization. Natural agonists consisting of nucleic acids, such as ssRNA or DNA with CpG motifs, activate the innate immune cells through these TLRs. Immune response modifiers (IRMs) of imidazoquinoline class compounds 3M-001, 3M-002, and 3M-003 have been shown to activate the innate immune system via TLR7, TLR8, and TLR7/8, respectively. In looking at the effect of the agonists of the TLR7, TLR8, and TLR9 on the activation of NF-kappaB of transfected HEK cells, we discovered that some oligodeoxynucleotides (ODNs) could modulate imidazoquinoline effects in a negative or positive manner. In this study we demonstrate that poly(T) ODNs can inhibit TLR7 and enhance TLR8 signaling events involving NF-kappaB activation in HEK cells and cytokine production (IFN-alpha, TNF, and IL-12) by human primary PBMC. In contrast, TLR3 agonist poly(I:C) does not affect imidazoquinoline-induced responses. The modulation of TLR7 and TLR8 responses is independent of CpG motifs or the nature of the ODN backbone structure. Furthermore, we show that to be an effective modulator, the ODNs need to be in the cell at the same time with either of the TLR7 or TLR8 agonist. We have also demonstrated that there is a physical interaction between IRMs and ODNs. The cross-talk between ODNs, IRMs, and TLR7 and TLR8 uncovered by this study may have practical implications in the field of microbial infections, vaccination, and tumor therapy.
Gorden
Keith K B
KK
Department of Pharmacology, 3M Pharmaceuticals, St. Paul, MN 55144, USA.
Qiu
Xiaohong
X
Battiste
John J L
JJ
Wightman
Paul P D
PP
Vasilakos
John P
JP
Alkan
Sefik S
SS
D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D009841:Oligonucleotides / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000276:immunology / Q000378:metabolism*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology / Q000378:metabolism; D014162:Transfection
D016207:Cytokines; D048289:Imidazolidines; D016328:NF-kappa B; D009841:Oligonucleotides; C495348:TLR7 protein, human; C495349:TLR8 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D051217:Toll-Like Receptor 9