Cutting Edge: Differential inhibition of TLR signaling pathways by cell-permeable peptides representing BB loops of TLRs.
We designed cell-penetrating peptides comprised of the translocating segment of Drosophila antennapedia homeodomain fused with BB loop sequences of TLR2, TLR4, and TLR1/6. TLR2- and TLR4-BB peptides (BBPs) inhibited NF-kappaB translocation and early IL-1beta mRNA expression induced by LPS, and the lipopeptides S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-N-palmitoyl-(R)-Cys-Ser-Lys(4)-OH (P3C) and S-[2,3-bis(palmitoyloxy)-(2-RS)-propyl]-Cys-Ser-Lys(4)-OH (P2C). TLR4- and TLR2-BBPs also strongly inhibited LPS-induced activation of ERK. Only TLR2-BBP significantly inhibited ERK activation induced by P3C, which acts via TLR2/1 heterodimers. BBPs did not inhibit activation of ERK induced by P2C, a TLR2/6 agonist. The TLR2-BBP induced weak activation of p38, but not ERK or cytokine mRNA. The TLR1/6-BBP failed to inhibit NF-kappaB or MAPK activation induced by any agonist. Our results suggest that the receptor BBPs selectively affect different TLR signaling pathways, and that the BB loops of TLR1/6 and TLR2 play distinct roles in formation of receptor heterodimers and recruitment of adaptor proteins.
Toshchakov
Vladimir Y
VY
Department of Microbiology and Immunology, University of Maryland-Baltimore, 660 West Redwood Street, Baltimore, MD 21201, USA.
Fenton
Matthew J
MJ
Vogel
Stefanie N
SN
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D004330:Drosophila / Q000276:immunology; D004789:Enzyme Activation / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology; D008074:Lipoproteins / Q000276:immunology* / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000276:immunology*; D051379:Mice; D050506:Mutant Chimeric Proteins / Q000276:immunology* / Q000494:pharmacology; D016328:NF-kappa B / Q000276:immunology; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology
D008074:Lipoproteins; D050506:Mutant Chimeric Proteins; D016328:NF-kappa B; D010455:Peptides; D051193:Toll-Like Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases