title: STAT1 deficiency redirects IFN signalling toward suppression of TLR response through a feedback activation of STAT3.
abstract: Interferons (IFNs) potentiate macrophage activation typically via a STAT1-dependent pathway. Recent studies suggest a functioning of STAT1-independent pathway in the regulation of gene expression by IFN-γ, thus pointing to the diversity in cellular responses to IFNs. Many functions of IFNs rely on cross-regulation of the responses to exogenous inflammatory mediators such as TLR ligands. Here we investigated the contribution of STAT1-independent pathway to macrophage activation and its underlying mechanism in the context of combined stimulation of IFN and TLR. We found that TLR-induced production of inflammatory cytokines (TNF-α, IL-12) was not simply nullified but was significantly suppressed by signaling common to IFN-γ and IFN-β in STAT1-null macrophages. Such a shift in the suppression of TLR response correlated with a sustained STAT3 activation and attenuation of NF-κB signaling. Using a JAK2/STAT3 pathway inhibitor or STAT3-specific siRNA, blocking STAT3 in that context restored TNF-α production and NF-κB signaling, thus indicating a functional cross-regulation among STAT1, STAT3, and NF-κB. Our results suggest that STAT1 deficiency reprograms IFN signaling from priming toward suppression of TLR response via feedback regulation of STAT3, which may provide a new insight into the host defense response against microbial pathogens in a situation of STAT1 deficiency.
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Cellular Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Department of Microbiology, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Hun Sik
authors: HS
authors: Kim
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Dong Chan
authors: DC
authors: Kim
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Hong-Mi
authors: HM
authors: Kim
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Cellular Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Hyung-Joon
authors: HJ
authors: Kwon
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Soon Jae
authors: SJ
authors: Kwon
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea.
authors: Suk-Jo
authors: SJ
authors: Kang
authors: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Korea.
authors: Sun Chang
authors: SC
authors: Kim
authors: Department of Biomedical Sciences, University of Ulsan College of Medicine, Seoul 138-736, Korea.|Cellular Dysfunction Research Center, University of Ulsan College of Medicine, Seoul 138-736, Korea.
authors: Go-Eun
authors: GE
authors: Choi
mesh_terms: D000818:Animals; D025461:Feedback, Physiological; D005260:Female; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000172:deficiency* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016328:NF-kappa B; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma