Tolerance induced via TLR2 and TLR4 in human dendritic cells: role of IRAK-1.
BACKGROUND
While dendritic cells (DCs) can induce tolerance in T cells, little is known about tolerance induction in DCs themselves. We have analysed tolerance induced in human in-vitro generated DCs by repeated stimulation with ligands for TLR4 and TLR2.


RESULTS
DCs stimulated with the TLR4 ligand LPS did show a rapid and pronounced expression of TNF mRNA and protein. When DCs were pre-cultured for 2 days with 5 ng LPS/ml then the subsequent response to stimulation with a high dose of LPS (500 ng/ml) was strongly reduced for both TNF mRNA and protein. At the promoter level there was a reduced transactivation by the -1173 bp TNF promoter and by a construct with a tetrameric NF-kappaB motif. Within the signalling cascade leading to NF-kappaB activation we found an ablation of the IRAK-1 adaptor protein in LPS-tolerant DCs. Pre-culture of DCs with the TLR2 ligand Pam3Cys also led to tolerance with respect to TNF gene expression and IRAK-1 protein was ablated in such tolerant cells as well, while IRAK-4 protein levels were unchanged.


CONCLUSIONS
These data show that TLR-ligands can render DCs tolerant with respect to TNF gene expression by a mechanism that likely involves blockade of signal transduction at the level of IRAK-1.
Albrecht
Valerie
V
Helmholtz Center München, German Research Center for Environmental Health and Asklepios-Fachkliniken Gauting, Inflammatory Lung Diseases, 82131 Gauting, Germany. valerie.albrecht@med.uni-muenchen.de
Hofer
Thomas P J
TP
Foxwell
Brian
B
Frankenberger
Marion
M
Ziegler-Heitbrock
Loems
L
D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology*; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D016328:NF-kappa B / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology
D008070:Lipopolysaccharides; D016328:NF-kappa B; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases