Cutting edge: species-specific TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modified oligonucleotides.
Different DNA motifs are required for optimal stimulation of mouse and human immune cells by CpG oligodeoxynucleotides (ODN). These species differences presumably reflect sequence differences in TLR9, the CpG DNA receptor. In this study, we show that this sequence specificity is restricted to phosphorothioate (PS)-modified ODN and is not observed when a natural phosphodiester backbone is used. Thus, human and mouse cells have not evolved to recognize different CpG motifs in natural DNA. Nonoptimal PS-ODN (i.e., mouse CpG motif on human cells and vice versa) gave delayed and less sustained phosphorylation of p38 MAPK than optimal motifs. When the CpG dinucleotide was inverted to GC in each ODN, some residual activity of the PS-ODN was retained in a species-specific, TLR-9-dependent manner. Thus, TLR9 may be responsible for mediating many published CpG-independent responses to PS-ODN.
Roberts
Tara L
TL
Institute for Molecular Bioscience, Cooperative Research Centre for Chronic Inflammatory Diseases, University of Queensland, Brisbane, Australia.
Sweet
Matthew J
MJ
Hume
David A
DA
Stacey
Katryn J
KJ
D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000276:immunology*; D004277:DNA, Single-Stranded / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000276:immunology; D020862:GC Rich Sequence / Q000276:immunology; D006801:Humans; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D013045:Species Specificity; D013873:Thionucleotides / Q000276:immunology / Q000378:metabolism*; D051217:Toll-Like Receptor 9
D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D004277:DNA, Single-Stranded; D004268:DNA-Binding Proteins; D009838:Oligodeoxyribonucleotides; D011956:Receptors, Cell Surface; C495371:TLR9 protein, human; D013873:Thionucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9