Immunostimulatory activity of Toll-like receptor 8 agonists towards human leucocytes: basic mechanisms and translational opportunities.
TLR8 (Toll-like receptor 8) is activated by ssRNAs (single-stranded RNAs) and synthetic imidazoquinoline compounds that resemble purines and have immunostimulatory activity. TLR8 agonists are particularly effective at inducing Th1-polarizing responses from human monocytes and myeloid dendritic cells, with the magnitude of response substantially exceeding that induced by agonists of other TLRs. Mechanisms underlying the remarkable efficacy of TLR8 agonists may include: (i) particularly robust activation of intracellular signalling cascades culminating in nuclear translocation of NF-kappaB (nuclear factor kappaB), (ii) activation of BTK (Bruton's tyrosine kinase), and (iii) the ability of some imidazoquinolines to induce TLR-independent effects via antagonism of adenosine receptors. The strong agonist activities of TLR8 agonists also extend to human neonatal leucocytes, which usually display impaired Th1-polarizing responses to many diverse stimuli including agonists of other TLRs. Their strong Th1-polarizing properties render TLR8 agonists attractive targets of biopharmaceutical development as agents that may induce protective immune responses in diverse populations, including newborns.
Philbin
V J
VJ
Department of Medicine, Division of Infectious Diseases, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. victoria.philbin@childrens.harvard.edu
Levy
O
O
D000818:Animals; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects* / Q000276:immunology; D018448:Models, Immunological; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012313:RNA / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000819:agonists* / Q000235:genetics / Q000276:immunology
D007093:Imidazoles; D011804:Quinolines; D051200:Toll-Like Receptor 8; D012313:RNA