IRF-8/interferon (IFN) consensus sequence-binding protein is involved in Toll-like receptor (TLR) signaling and contributes to the cross-talk between TLR and IFN-gamma signaling pathways.
Toll-like receptor (TLR) and interferon-gamma (IFN-gamma) signaling pathways are important for both innate and adaptive immune responses. However, the cross-talk between these two signaling pathways is incompletely understood. Here we show that IFN-gamma and LPS synergistically induce the expression of proinflammatory factors, including interleukin-1 (IL-1), IL-6, IL-12, NO, and tumor ... necrosis factor-alpha (TNF-alpha). Comparable synergism was observed between IFN-gamma and peptidoglycan (PGN; a TLR2 ligand) and poly(I:C) (a TLR3 ligand) in the induction of IL-12 promoter activity. IFN-gamma enhanced lipopolysaccharide (LPS)-induced ERK and JNK phosphorylation but had no effect on LPS-induced NF-kappaB activation. Interestingly, we found that IRF-8-/- macrophages were impaired in the activation of LPS-induced ERK and JNK and the production of proinflammatory cytokines induced by LPS or IFN-gamma plus LPS. Retroviral transduction of IRF-8 into IRF-8-/- macrophages rescued ERK and JNK activation. Furthermore, co-immunoprecipitation experiments show that IRF-8 physically interacts with TRAF6 at a binding site between amino acid residues 356 and 305 of IRF-8. Transfection of IRF-8 enhanced TRAF6 ubiquitination, which is consistent with a physical interaction of IRF-8 with TRAF6. Taken together, the results suggest that the interaction of IRF-8 with TRAF6 modulates TLR signaling and may contribute to the cross-talk between IFN-gamma and TLR signal pathways.
Mesh Terms:
Cell Line, Cytokines, Humans, Immune System, Immunoprecipitation, Interferon Regulatory Factors, Interferon-gamma, Interferons, Ligands, Lipopolysaccharides, Macrophages, NF-kappa B, Peptidoglycan, Peritoneum, Phosphorylation, Plasmids, Protein Binding, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 6, Time Factors, Toll-Like Receptors, Transfection, Tumor Necrosis Factor-alpha
Cell Line, Cytokines, Humans, Immune System, Immunoprecipitation, Interferon Regulatory Factors, Interferon-gamma, Interferons, Ligands, Lipopolysaccharides, Macrophages, NF-kappa B, Peptidoglycan, Peritoneum, Phosphorylation, Plasmids, Protein Binding, Retroviridae, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, TNF Receptor-Associated Factor 6, Time Factors, Toll-Like Receptors, Transfection, Tumor Necrosis Factor-alpha
J. Biol. Chem.
Date: Apr. 14, 2006
PubMed ID: 16484229
View in: Pubmed Google Scholar
Download Curated Data For This Publication
101776
Switch View:
- Interactions 2
- PTM Genes 1