Abstract
Adaptive immune responses by dendritic cells (DCs) are critically controlled by Toll-like receptor (TLR) function. Little is known about modulation of TLR-specific signaling by other pathogen receptors. Here, we have identified a molecular signaling pathway induced by the C-type lectin DC-SIGN that modulates TLR signaling at the level of the transcription factor NF-kappaB. We demonstrated that pathogens trigger DC-SIGN on human DCs to activate the serine and threonine kinase Raf-1, which subsequently leads to acetylation of the NF-kappaB subunit p65, but only after TLR-induced activation of NF-kappaB. Acetylation of p65 both prolonged and increased IL10 transcription to enhance anti-inflammatory cytokine responses. We demonstrated that different pathogens such as Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and human immunodeficiency virus-1 interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs. Thus, this pathway is involved in regulation of adaptive immunity by DCs to bacterial, fungal, and viral pathogens.
Original language | English |
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Pages (from-to) | 605-16 |
Number of pages | 12 |
Journal | Immunity |
Volume | 26 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2007 |
Keywords
- Acetylation
- Amino Acid Motifs
- Cell Adhesion Molecules/genetics
- Cells, Cultured
- DNA/metabolism
- Enzyme Activation
- Humans
- Interleukin-10/biosynthesis
- Lectins, C-Type/genetics
- NF-kappa B/metabolism
- Phosphoserine/metabolism
- Protein Binding
- Protein-Serine-Threonine Kinases/metabolism
- Proto-Oncogene Proteins c-raf/metabolism
- Receptors, Antigen, T-Cell/metabolism
- Receptors, Cell Surface/genetics
- Signal Transduction
- Toll-Like Receptor 3/metabolism
- Toll-Like Receptor 4/metabolism
- Toll-Like Receptor 5/metabolism
- Toll-Like Receptors/metabolism
- Transcription, Genetic/genetics
- ras Proteins/metabolism