TY - JOUR
T1 - Microbial products stimulate human toll-like receptor 2 expression through histone modification surrounding a proximal NF-κB-binding site
AU - Johnson, Christopher M.
AU - Tapping, Richard I.
PY - 2007/10/26
Y1 - 2007/10/26
N2 - Previous studies have yielded conflicting results regarding the ability of microbial products to activate TLR2 gene expression in human monocytes. In this study, we found that TLR2 mRNA was rapidly up-regulated in human monocytes treated with TLR2 and TLR4 agonists, and this corresponded to an increase in cell surface receptor levels. This induction was abrogated by actinomycin D as well as a pharmacologic inhibitor of NF-κB, suggesting that the TLR2 gene is transcriptionally activated via NF-κB. Microbial agonists were found to shift the transcription initiation site of the TLR2 gene, and sequence examination revealed a near-consensus NF-κB-binding element immediately upstream of this site. Electromobility shift assays confirmed that NF-κB bound to this putative site in vitro. However, luciferase reporter plasmids driven by the TLR2 promoter were not responsive to TLR2 agonists. Overexpression of the NF-κB p65 subunit was sufficient to induce expression of the endogenous TLR2 mRNA, and co-transfection of the CREB-binding protein and p300 co-activators further increased TLR2 mRNA levels. Chromatin immunoprecipitation analysis revealed that p65, CREB-binding protein, and p300 are recruited to the TLR2 promoter upon stimulation of human monocytes followed by histone hyperacetylation. Taken together, these results define a mechanism whereby histone modification and increased promoter access induce expression of human TLR2 following infection.
AB - Previous studies have yielded conflicting results regarding the ability of microbial products to activate TLR2 gene expression in human monocytes. In this study, we found that TLR2 mRNA was rapidly up-regulated in human monocytes treated with TLR2 and TLR4 agonists, and this corresponded to an increase in cell surface receptor levels. This induction was abrogated by actinomycin D as well as a pharmacologic inhibitor of NF-κB, suggesting that the TLR2 gene is transcriptionally activated via NF-κB. Microbial agonists were found to shift the transcription initiation site of the TLR2 gene, and sequence examination revealed a near-consensus NF-κB-binding element immediately upstream of this site. Electromobility shift assays confirmed that NF-κB bound to this putative site in vitro. However, luciferase reporter plasmids driven by the TLR2 promoter were not responsive to TLR2 agonists. Overexpression of the NF-κB p65 subunit was sufficient to induce expression of the endogenous TLR2 mRNA, and co-transfection of the CREB-binding protein and p300 co-activators further increased TLR2 mRNA levels. Chromatin immunoprecipitation analysis revealed that p65, CREB-binding protein, and p300 are recruited to the TLR2 promoter upon stimulation of human monocytes followed by histone hyperacetylation. Taken together, these results define a mechanism whereby histone modification and increased promoter access induce expression of human TLR2 following infection.
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U2 - 10.1074/jbc.M705151200
DO - 10.1074/jbc.M705151200
M3 - Article
C2 - 17728249
AN - SCOPUS:35748983841
SN - 0021-9258
VL - 282
SP - 31197
EP - 31205
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 43
ER -