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Albrecht, V. ; Hofer, T.P. ; Foxwell, B.* ; Frankenberger, M. ; Ziegler-Heitbrock, L.

Tolerance induced via TLR2 and TLR4 in human dendritic cells: Role of IRAK-1.

BMC Immunol. 9:69 (2008)
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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 bot 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. 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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords NF-KAPPA-B; RECEPTOR-ASSOCIATED KINASE; NECROSIS-FACTOR-ALPHA; RECURRENT BACTERIAL-INFECTIONS; ENDOTOXIN TOLERANCE; HUMAN MONOCYTES; LIPOPOLYSACCHARIDE TOLERANCE; C/EBP-BETA; MURINE MACROPHAGES; LIPOTEICHOIC ACID
e-ISSN 1471-2172
Journal BMC Immunology
Quellenangaben Volume: 9, Issue: , Pages: , Article Number: 69 Supplement: ,
Publisher BioMed Central
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)