Crosstalk Between IFN-γ and TLR

Abstract

Zhao et al. noted that when peritoneal macrophages were exposed to both interferon-γ (IFN-γ) and a ligand for Toll-like receptors (TLRs) such as lipopolysaccharide (LPS), the ligand for TLR-4, the expression and secretion of proinflammatory mediators was enhanced compared with that in cells exposed to either class of ligand alone. Synergism was also observed in an interleukin-12 (IL-12) reporter gene assay between IFN-γ and ligands for TLR-2 [peptidoglycan (PGN)] and TLR-3 (polyI:C). The activation of the extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) pathways by LPS was enhanced by application of both IFN-γ and LPS, whereas activation of the nuclear factor κB (NF-κB) pathway by LPS was not changed by the addition of IFN-γ. LPS stimulated an increase in the abundance of interferon regulator factor 8 (IRF8), and cells deficient for IRF8 showed lower production of inflammatory mediators and were deficient in ERK and JNK activation in response to LPS, PGN, or polyI:C. Introduction of IRF8 or an IRF8 mutant that lacked DNA binding activity into the knockout cells restored the activation of ERK by LPS. IRF8 and TRAF6, a ubiquitin ligase involved in TLR signaling, coimmunoprecipitated from either transfected cells or LPS-stimulated peritoneal macrophages. In transfected cells, IRF8 enhanced ubiquitination of TRAF6, and TRAF6 ubiquitination was reduced in the IRF8 knockout cells. Thus, in addition to its role in stimulating gene expression in response to IFN-γ, IRF8 also enhances signaling through the TLR family of receptors by interacting with and stimulating TRAF6. J. Zhao, H. J. Kong, H. Li, B. Huang, M. Yang, C. Zhu, M. Bogunovic, F. Zheng, L. Mayer, K. Ozato, J. Unkeless, H. Xiong, 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-γ signaling pathways. J. Biol. Chem. 281 , 10073-10080 (2006). [Abstract] [Full Text]