STAT-1 alpha and IFN-gamma as modulators of TNF-alpha signaling in macrophages: regulation and functional implications of the TNF receptor 1:STAT-1 alpha complex.
TNF-alpha and IFN-gamma cooperate in the activation of macrophages. TNF-alpha-dependent activation of NF-kappaB is stronger in the presence of IFN-gamma. STAT-1alpha associates with TNFR1 in TNF-alpha-treated cells, and this association attenuates TNF-alpha-mediated NF-kappaB activation. We hypothesized that nuclear localization of STAT-1alpha due to IFN-gamma signaling would preclude it from being recruited to the TNFR1 and therefore enhance TNF-alpha-induced NF-kappaB activation. In the RAW264.7 macrophage cell line, TNF-alpha treatment indeed recruits STAT-1alpha to the TNFR1, and this association is abrogated when cells are exposed to IFN-gamma. TNF-alpha treatment induces a more robust activation of NF-kappaB in STAT-1alpha-deficient cells, and restoration of STAT-1alpha inhibits TNF-alpha-dependent NF-kappaB activation. Our results suggest that a receptor-proximal level of cross-talk exists between these two cytokine pathways: IFN-gamma limits STAT-1alpha availability to the TNFR1 by depleting STAT-1alpha from the cytoplasm, thus allowing for optimal NF-kappaB activation upon TNF-alpha ligation.
Wesemann
Duane R
DR
Department of Cell Biology, University of Alabama, Birmingham, AL 35294, USA.
Benveniste
Etty N
EN
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism / Q000502:physiology*; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004357:Drug Synergism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology; D050832:Interferon-Stimulated Gene Factor 3; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D046911:Macromolecular Substances; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*
D015703:Antigens, CD; D018836:Inflammation Mediators; D050832:Interferon-Stimulated Gene Factor 3; D046911:Macromolecular Substances; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012097:Repressor Proteins; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C079868:gamma interferon activation factor; D007371:Interferon-gamma