Toll-like receptors differentially induce nucleosome remodelling at the IL-12p40 promoter.
Toll-like receptors (TLRs) mediate recognition of microbial components. Despite activation of a shared set of signal transduction molecules, the biological effects of certain TLR agonists differ considerably. In macrophages and dendritic cells, stimulation by the prototypical stimuli CpG-DNA (TLR9), lipopolysaccharide (LPS; TLR4) and lipoteichoic acid (LTA; TLR2) resulted in striking differences in expression of IL-12. However, these stimuli induced similar amounts of the common proinflammatory cytokine TNFalpha. Surprisingly, an IL-12p40 promoter reporter construct was activated equally by CpG-DNA, LPS and LTA. Examinations of the chromatin structure of the endogenous IL-12p40 promoter revealed that nucleosome remodelling contributed to differential IL-12 induction. Upon stimulation, nucleosome architecture was changed to provide increased access to the IL-12p40 promoter. In dendritic cells, a differential induction of nucleosome remodelling at the IL-12p40 promoter was observed upon triggering with different TLR agonists. These results identify nucleosome remodelling as an additional restriction point in differential TLR signalling.
Albrecht
Inka
I
Institute of Medical Microbiology and Hygiene, Philipps-University Marburg, Pilgrimstein 2, D-35037 Marburg, Germany.
Tapmeier
Thomas
T
Zimmermann
Stefan
S
Frey
Markus
M
Heeg
Klaus
K
Dalpke
Alexander
A
D000818:Animals; D018929:Cell Culture Techniques; D003713:Dendritic Cells / Q000378:metabolism; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009707:Nucleosomes / Q000235:genetics* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D013682:Teichoic Acids / Q000494:pharmacology; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C408982:CPG-oligonucleotide; D053762:Interleukin-12 Subunit p40; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D009707:Nucleosomes; D009838:Oligodeoxyribonucleotides; D021122:Protein Subunits; D011956:Receptors, Cell Surface; D013682:Teichoic Acids; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014157:Transcription Factors; D018664:Interleukin-12; C009900:lipoteichoic acid