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.
Immunobiology Center, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Jie
J
Zhao
Hee Jeong
HJ
Kong
Hongxing
H
Li
Bo
B
Huang
Min
M
Yang
Chen
C
Zhu
Milena
M
Bogunovic
Feng
F
Zheng
Lloyd
L
Mayer
Keiko
K
Ozato
Jay
J
Unkeless
Huabao
H
Xiong
D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007107:Immune System / Q000378:metabolism; D047468:Immunoprecipitation; D050835:Interferon Regulatory Factors / Q000737:chemistry* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism*; D007372:Interferons / Q000737:chemistry*; D008024:Ligands; D008070:Lipopolysaccharides / Q000737:chemistry; D008264:Macrophages / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010457:Peptidoglycan / Q000737:chemistry; D010537:Peritoneum / Q000473:pathology; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D013997:Time Factors; D051193:Toll-Like Receptors / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
D016207:Cytokines; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D007372:Interferons; D008024:Ligands; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010457:Peptidoglycan; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D000099185:Interferon Regulatory Factor-8; C109803:IRF6 protein, human