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

• Published in: BMC immunology Vol. 9; no. 1; p. 69
• Main Authors: Albrecht, Valerie, Hofer, Thomas P J, Foxwell, Brian, Frankenberger, Marion, Ziegler-Heitbrock, Loems
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 24.11.2008; BioMed Central; BMC
• Subjects: Cell receptors; Cells, Cultured; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Genetic aspects; Health aspects; Humans; Immune Tolerance; Immunological tolerance; Interleukin-1 Receptor-Associated Kinases - immunology; Interleukin-12 - immunology; Interleukin-12 - metabolism; Lipopolysaccharides - immunology; NF-kappa B - drug effects; NF-kappa B - immunology; NF-kappa B - metabolism; Physiological aspects; Protein kinases; Signal Transduction; Toll-Like Receptor 2 - agonists; Toll-Like Receptor 2 - immunology; Toll-Like Receptor 4 - agonists; Toll-Like Receptor 4 - immunology; Tumor Necrosis Factor-alpha - drug effects; Tumor Necrosis Factor-alpha - immunology; Germany
• ISSN: 1471-2172; 1471-2172
• DOI: 10.1186/1471-2172-9-69

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. 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. 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.