Toll-like receptor 9 signaling activates NF-kappaB through IFN regulatory factor-8/IFN consensus sequence binding protein in dendritic cells.
Unmethylated CpG DNA binds to the Toll-like receptor 9 (TLR9) and activates NF-kappaB to induce cytokine genes in dendritic cells (DCs). IFN regulatory factor (IRF)-8/IFN consensus sequence binding protein is a transcription factor important for development and activation of DCs. We found that DCs from IRF-8(-/-) mice were unresponsive to CpG and failed to induce TNF-alpha and IL-6, targets of NF-kappaB. Revealing a signaling defect selective for CpG, these cytokines were robustly induced in IRF-8(-/-) DCs in response to LPS that signals through TLR4. IRF-8(-/-) DCs expressed TLR9, adaptor myeloid differentiation factor 88, and other signaling molecules, but CpG failed to activate NF-kappaB in -/- cells. This was due to the selective inability of -/- DCs to activate I-kappaB kinase alphabeta, the kinases required for NF-kappaB in response to CpG. IRF-8 reintroduction fully restored CpG activation of NF-kappaB and cytokine induction in -/- DCs. Together, TLR signals that activate NF-kappaB are diverse among different TLRs, and TLR9 signaling uniquely depends on IRF-8 in DCs.
Tsujimura
Hideki
H
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
Tamura
Tomohiko
T
Kong
Hee Jeong
HJ
Nishiyama
Akira
A
Ishii
Ken J
KJ
Klinman
Dennis M
DM
Ozato
Keiko
K
D003713:Dendritic Cells / Q000502:physiology*; D022761:Gene Transfer, Horizontal; D006801:Humans; D051550:I-kappa B Kinase; D050835:Interferon Regulatory Factors; D015850:Interleukin-6 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases; D000099185:Interferon Regulatory Factor-8
D051550:I-kappa B Kinase; D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D017346:Protein Serine-Threonine Kinases; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099185:Interferon Regulatory Factor-8; C408982:CPG-oligonucleotide; C495345:TLR4 protein, human; C495371:TLR9 protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human