Journal
BMC IMMUNOLOGY
Volume 9, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1471-2172-9-69
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Funding
- Deutsche Forschungs-gemeinschaft (DFG) [Zi 288/2-3, Zi 288/2-4]
- Arthritis Research Campaign, UK
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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-kappa B motif. Within the signalling cascade leading to NF-kappa B 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. Conclusion: 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.
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