Kinetic of RelA activation controls magnitude of TLR-mediated IL-12p40 induction.
IL-12 is a crucial cytokine for dendritic cell-mediated induction of Th 1 cell differentiation. TLR ligands induce IL-12 to differing extents. Stimulation of dendritic cells allowed for the differentiation of three groups of TLRs; potency to induce IL-12 decreased in the order of TLR7/9, TLR3/4, and TLR1/2/6 stimulation. The MAPK, PI3K, and IRF (IFN regulatory factor) signaling pathways could be ruled out to be the cause for the differences in IL-12p40 induction. However, we observed that stimulation of dendritic cells with different TLR ligands resulted in striking differences in the kinetics of NF-kappaB activation. LPS induced a rapid but short-lived activation of RelA, whereas CpG-DNA stimulation resulted in prolonged RelA activity at the IL-12p40 promoter. Only TLR2 and TLR4 ligands were capable of inducing S536 phosphorylation of RelA, which has been proposed to be responsible for early termination of NF-kappaB activation. It is suggested that differences in the kinetics of a common TLR signaling module affect the biological response patterns of various TLRs, with IL-12p40 being a gene that needs prolonged NF-kappaB activation.
Bode
Konrad A
KA
Department of Medical Microbiology and Hygiene, University of Heidelberg, Heidelberg, Germany.
Schmitz
Frank
F
Vargas
Leonardo
L
Heeg
Klaus
K
Dalpke
Alexander H
AH
D000818:Animals; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D047468:Immunoprecipitation; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis* / Q000235:genetics; D008024:Ligands; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000819:agonists*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
D053762:Interleukin-12 Subunit p40; D008024:Ligands; D016328:NF-kappa B; C498144:Rela protein, mouse; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA