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J. Biol. Chem. 281 (15): 10073-10080

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

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*

Jie Zhao{ddagger}, Hee Jeong Kong§, Hongxing Li{ddagger}, Bo Huang, Min Yang{ddagger}1, Chen Zhu||, Milena Bogunovic{ddagger}, Feng Zheng**, Lloyd Mayer{ddagger}, Keiko Ozato§, Jay Unkeless{ddagger}2, , and Huabao Xiong{ddagger}23

{ddagger}Immunobiology Center, Mount Sinai School of Medicine, New York, New York 10029, §Laboratory of Molecular Growth and Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, the Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, New York 10029, ||Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and the **Department of Geriatrics, Mount Sinai School of Medicine, New York, New York 10029

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-{kappa}B 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.

Received for publication July 18, 2005. Revision received February 15, 2006.

* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by an Extended Fellowship from the Systemic Lupus Erythematosus Foundation.

2 Supported by Crohn's and Colitis Foundation of America and the Cullman Family.

3 To whom correspondence should be addressed: Immunobiology Center, Box 1630, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029-6574. Tel.: 212-659-9413; Fax: 212-849-2525; E-mail: Huabao.Xiong{at}mssm.edu.

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