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.

• 发表时间: Apr 2006 14
• 来源期刊: J Biol Chem
• DOI: 10.1074/jbc.M507788200
• PMID: 16484229
• 文章类型: Journal Article
• 中科院分区: Q2
• 方向: 生物
• 作者列表: Zhao J,Kong HJ,Li H,Huang B,Yang M,Zhu C,Bogunovic M,Zheng F,Mayer L,Ozato K,Unkeless J,Xiong H

Mesh: Cell Line; Cytokines / metabolism; Humans; Immune System / metabolism; Immunoprecipitation; Interferon Regulatory Factors / chemistry metabolism; Interferon-gamma / metabolism; Interferons / chemistry; Ligands; Lipopolysaccharides / chemistry; Macrophages / metabolism; NF-kappa B / metabolism; Peptidoglycan / chemistry; Peritoneum / pathology; Phosphorylation; Plasmids / metabolism; Protein Binding; Retroviridae / genetics metabolism; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; TNF Receptor-Associated Factor 6 / metabolism; Time Factors; Toll-Like Receptors / metabolism; Transfection; Tumor Necrosis Factor-alpha / metabolism

Abstract

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.