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BMC Immunology

, 9:69

First Online: 24 November 2008Received: 26 March 2008Accepted: 24 November 2008


BackgroundWhile 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.

ResultsDCs 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-κB motif. Within the signalling cascade leading to NF-κB 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.

ConclusionThese 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.

AbbreviationsDCdendritic cell

TLRtoll like receptor


IRAKinterleukin-1 receptor associated kinases

TNFtumour necrosis factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2172-9-69 contains supplementary material, which is available to authorized users.

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Autor: Valerie Albrecht - Thomas PJ Hofer - Brian Foxwell - Marion Frankenberger - Loems Ziegler-Heitbrock


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